Publications by authors named "Tamotsu Yoshimori"

206 Publications

Rubicon in Metabolic Diseases and Ageing.

Front Cell Dev Biol 2021 10;9:816829. Epub 2022 Jan 10.

Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Japan.

Autophagy is a conserved cellular degradation system that maintains intracellular homeostasis. Cytoplasmic components are engulfed into double-membrane vesicles called autophagosomes, which fuse with lysosomes, and resulting in the degradation of sequestered materials. Recently, a close association between autophagy and the pathogenesis of metabolic diseases and ageing has become apparent: autophagy is dysregulated during metabolic diseases and ageing; dysregulation of autophagy is intimately associated with the pathophysiology. Rubicon (Run domain Beclin-1 interacting and cysteine-rich containing protein) has been identified as a Beclin-1 associated protein. Notably, Rubicon is one of few negative regulators of autophagy whereas many autophagy-related genes are positive regulators of autophagy. Rubicon also has autophagy-independent functions including phagocytosis and endocytosis. In this mini-review, we focus on the various roles of Rubicon in different organs in the settings of metabolic diseases and ageing, and discuss its potential role as a promising therapeutic target.
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http://dx.doi.org/10.3389/fcell.2021.816829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8784836PMC
January 2022

Degradation of the NOTCH intracellular domain by elevated autophagy in osteoblasts promotes osteoblast differentiation and alleviates osteoporosis.

Autophagy 2022 Jan 13:1-10. Epub 2022 Jan 13.

Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.

Maintenance of bone integrity is mediated by the balanced actions of osteoblasts and osteoclasts. Because macroautophagy/autophagy regulates osteoblast mineralization, osteoclast differentiation, and their secretion from osteoclast cells, autophagy deficiency in osteoblasts or osteoclasts can disrupt this balance. However, it remains unclear whether upregulation of autophagy becomes beneficial for suppression of bone-associated diseases. In this study, we found that genetic upregulation of autophagy in osteoblasts facilitated bone formation. We generated mice in which autophagy was specifically upregulated in osteoblasts by deleting the gene encoding RUBCN/Rubicon, a negative regulator of autophagy. The mice showed progressive skeletal abnormalities in femur bones. Consistent with this, RUBCN deficiency in osteoblasts resulted in elevated differentiation and mineralization, as well as an increase in the elevated expression of key transcription factors involved in osteoblast function such as and . Furthermore, RUBCN deficiency in osteoblasts accelerated autophagic degradation of NOTCH intracellular domain (NICD) and downregulated the NOTCH signaling pathway, which negatively regulates osteoblast differentiation. Notably, osteoblast-specific deletion of RUBCN alleviated the phenotype in a mouse model of osteoporosis. We conclude that RUBCN is a key regulator of bone homeostasis. On the basis of these findings, we propose that medications targeting RUBCN or autophagic degradation of NICD could be used to treat age-related osteoporosis and bone fracture.: ALPL: alkaline phosphatase, liver/bone/kidney; BCIP/NBT: 5-bromo-4-chloro-3'-indolyl phosphate/nitro blue tetrazolium; BMD: bone mineral density; BV/TV: bone volume/total bone volume; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NICD: NOTCH intracellular domain; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; SERM: selective estrogen receptor modulator; TNFRSF11B/OCIF: tumor necrosis factor receptor superfamily, member 11b (osteoprotegerin).
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http://dx.doi.org/10.1080/15548627.2021.2017587DOI Listing
January 2022

Rubicon-regulated beta-1 adrenergic receptor recycling protects the heart from pressure overload.

Sci Rep 2022 Jan 7;12(1):41. Epub 2022 Jan 7.

The School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, London, SE5 9NU, UK.

Heart failure has high morbidity and mortality in the developed countries. Autophagy is important for the quality control of proteins and organelles in the heart. Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein) has been identified as a potent negative regulator of autophagy and endolysosomal trafficking. The aim of this study was to investigate the in vivo role of Rubicon-mediated autophagy and endosomal trafficking in the heart. We generated cardiomyocyte-specific Rubicon-deficient mice and subjected the mice to pressure overload by means of transverse aortic constriction. Rubicon-deficient mice showed heart failure with left ventricular dilatation, systolic dysfunction and lung congestion one week after pressure overload. While autophagic activity was unchanged, the protein amount of beta-1 adrenergic receptor was decreased in the pressure-overloaded Rubicon-deficient hearts. The increases in heart rate and systolic function by beta-1 adrenergic stimulation were significantly attenuated in pressure-overloaded Rubicon-deficient hearts. In isolated rat neonatal cardiomyocytes, the downregulation of the receptor by beta-1 adrenergic agonist was accelerated by knockdown of Rubicon through the inhibition of recycling of the receptor. Taken together, Rubicon protects the heart from pressure overload. Rubicon maintains the intracellular recycling of beta-1 adrenergic receptor, which might contribute to its cardioprotective effect.
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http://dx.doi.org/10.1038/s41598-021-03920-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741968PMC
January 2022

Autophagy in major human diseases.

EMBO J 2021 10 30;40(19):e108863. Epub 2021 Aug 30.

Signalling Programme, Babraham Institute, Cambridge, UK.

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
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http://dx.doi.org/10.15252/embj.2021108863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488577PMC
October 2021

Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function.

PLoS Genet 2021 08 5;17(8):e1009688. Epub 2021 Aug 5.

Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

Autophagy degrades unnecessary proteins or damaged organelles to maintain cellular function. Therefore, autophagy has a preventive role against various diseases including hepatic disorders, neurodegenerative diseases, and cancer. Although autophagy in germ cells or Sertoli cells is known to be required for spermatogenesis and male fertility, it remains poorly understood how autophagy participates in spermatogenesis. We found that systemic knockout mice of Rubicon, a negative regulator of autophagy, exhibited a substantial reduction in testicular weight, spermatogenesis, and male fertility, associated with upregulation of autophagy. Rubicon-null mice also had lower levels of mRNAs of Sertoli cell-related genes in testis. Importantly, Rubicon knockout in Sertoli cells, but not in germ cells, caused a defect in spermatogenesis and germline stem cell maintenance in mice, indicating a critical role of Rubicon in Sertoli cells. In mechanistic terms, genetic loss of Rubicon promoted autophagic degradation of GATA4, a transcription factor that is essential for Sertoli cell function. Furthermore, androgen antagonists caused a significant decrease in the levels of Rubicon and GATA4 in testis, accompanied by elevated autophagy. Collectively, we propose that Rubicon promotes Sertoli cell function by preventing autophagic degradation of GATA4, and that this mechanism could be regulated by androgens.
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http://dx.doi.org/10.1371/journal.pgen.1009688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341604PMC
August 2021

Regulatory Mechanisms of Autophagy-Targeted Antimicrobial Therapeutics Against Mycobacterial Infection.

Front Cell Infect Microbiol 2021 22;11:633360. Epub 2021 Mar 22.

Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea.

(Mtb) is an intracellular pathogen causing human tuberculosis, an infectious disease that still remains as a global health problem. Autophagy, a lysosomal degradative process, has emerged as a critical pathway to restrict intracellular Mtb growth through enhancement of phagosomal maturation. Indeed, several autophagy-modulating agents show promise as host-directed therapeutics for Mtb infection. In this Review, we discuss recent progress in our understanding the molecular mechanisms underlying the action of autophagy-modulating agents to overcome the immune escape strategies mediated by Mtb. The factors and pathways that govern such mechanisms include adenosine 5'-monophosphate-activated protein kinase, Akt/mammalian TOR kinase, Wnt signaling, transcription factor EB, cathelicidins, inflammation, endoplasmic reticulum stress, and autophagy-related genes. A further understanding of these mechanisms will facilitate the development of host-directed therapies against tuberculosis as well as infections with other intracellular bacteria targeted by autophagic degradation.
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http://dx.doi.org/10.3389/fcimb.2021.633360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019938PMC
July 2021

Rubicon regulates A2E-induced autophagy impairment in the retinal pigment epithelium implicated in the pathology of age-related macular degeneration.

Biochem Biophys Res Commun 2021 04 16;551:148-154. Epub 2021 Mar 16.

Department of Ocular Immunology and Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka, Japan. Electronic address:

Waste product deposition and light stress in the retinal pigment epithelium (RPE) are crucial factors in the pathogenesis of various retinal degenerative diseases, including age-related macular degeneration (AMD), a leading cause of vision loss in elderly individuals worldwide. Given that autophagy in the RPE suppresses waste accumulation, determining the molecular mechanism by which autophagy is compromised in degeneration is necessary. Using polarized human RPE sheets, we found that bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), a major toxic fluorophore of lipofuscin, causes significant impairment of autophagy and the simultaneous upregulation of Rubicon, a negative regulator of autophagy. Importantly, this impairment was reversed in Rubicon-specific siRNA-treated RPE sheets. In a retinal functional analysis using electroretinograms (ERGs), mice with the RPE-specific deletion of Rubicon showed no significant differences from control cre-expressing mice but presented partially but significantly enhanced amplitudes compared with Atg7 knockout mice. We also found that an inflammatory reaction in the retina in response to chronic blue light irradiation was alleviated in mice with the RPE-specific deletion of Rubicon. In summary, we propose that upregulating basal autophagy by targeting Rubicon is beneficial for protecting the RPE from functional damage with ageing and the inflammatory reaction caused by light-induced cellular stress.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.148DOI Listing
April 2021

TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis.

Autophagy 2021 11 11;17(11):3776-3793. Epub 2021 Mar 11.

Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

Preconditioning with a mild stressor such as fasting is a promising way to reduce severe side effects from subsequent chemo- or radiotherapy. However, the underlying mechanisms have been largely unexplored. Here, we demonstrate that the TP53/p53-FBXO22-TFEB (transcription factor EB) axis plays an essential role in this process through upregulating basal macroautophagy/autophagy. Mild stress-activated TP53 transcriptionally induced FBXO22, which in turn ubiquitinated KDM4B (lysine-specific demethylase 4B) complexed with MYC-NCOR1 suppressors for degradation, leading to transcriptional induction of TFEB. Upregulation of autophagy-related genes by increased TFEB dramatically enhanced autophagic activity and cell survival upon following a severe stressor. Mitogen-induced AKT1 activation counteracted this process through the phosphorylation of KDM4B, which inhibited FBXO22-mediated ubiquitination. Additionally, mice died within 10 h of birth, and their mouse embryonic fibroblasts (MEFs) showed a lowered basal autophagy, whereas FBXO22-overexpressing mice were resistant to chemotherapy. Taken together, these results suggest that TP53 upregulates basal autophagy through the FBXO22-TFEB axis, which governs the hormetic effect in chemotherapy.: BBC3/PUMA: BCL2 binding component 3; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; ChIP-seq: chromatin immunoprecipitation followed by sequencing; DDB2: damage specific DNA binding protein 2; DRAM: DNA damage regulated autophagy modulator; ESR/ER: estrogen receptor 1; FMD: fasting mimicking diet; HCQ: hydroxychloroquine; KDM4B: lysine-specific demethylase 4B; MAP1LC3/LC3: microtubule associated protein 1 light chain 3 alpha; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; NCOR1: nuclear receptor corepressor 1; SCF: SKP1-CUL-F-box protein; SQSTM1: sequestosome 1; TFEB: transcription factor EB.
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http://dx.doi.org/10.1080/15548627.2021.1897961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632335PMC
November 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

THOC4 regulates energy homeostasis by stabilizing mRNA during prolonged starvation.

J Cell Sci 2021 03 22;134(6). Epub 2021 Mar 22.

Department of Genetics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan

TFEB, a basic helix-loop-helix transcription factor, is a master regulator of autophagy, lysosome biogenesis and lipid catabolism. Compared to posttranslational regulation of TFEB, the regulation of mRNA stability remains relatively uncharacterized. In this study, we identified the mRNA-binding protein THOC4 as a novel regulator of TFEB. In mammalian cells, siRNA-mediated knockdown of THOC4 decreased the level of TFEB protein to a greater extent than other bHLH transcription factors. THOC4 bound to mRNA and stabilized it after transcription by maintaining poly(A) tail length. We further found that this mode of regulation was conserved in and was essential for TFEB-mediated lipid breakdown, which becomes over-represented during prolonged starvation. Taken together, our findings reveal the presence of an additional layer of TFEB regulation by THOC4 and provide novel insights into the function of TFEB in mediating autophagy and lipid metabolism.
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http://dx.doi.org/10.1242/jcs.248203DOI Listing
March 2021

Vacuolar protein Tag1 and Atg1-Atg13 regulate autophagy termination during persistent starvation in .

J Cell Sci 2021 02 26;134(4). Epub 2021 Feb 26.

Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Yamadaoka 1-8, Suita, Osaka 565-0871, Japan

Under starvation conditions, cells degrade their own components via autophagy in order to provide sufficient nutrients to ensure their survival. However, even if starvation persists, the cell is not completely degraded through autophagy, implying the existence of some kind of termination mechanism. In the yeast , autophagy is terminated after 10-12 h of nitrogen starvation. In this study, we found that termination is mediated by re-phosphorylation of Atg13 by the Atg1 protein kinase, which is also affected by PP2C phosphatases, and the eventual dispersion of the pre-autophagosomal structure, also known as the phagophore assembly site (PAS). In a genetic screen, we identified an uncharacterized vacuolar membrane protein, Tag1, as a factor responsible for the termination of autophagy. Re-phosphorylation of Atg13 and eventual PAS dispersal were defective in the Δ mutant. The vacuolar luminal domain of Tag1 and autophagic progression are important for the behaviors of Tag1. Together, our findings reveal the mechanism and factors responsible for termination of autophagy in yeast.
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http://dx.doi.org/10.1242/jcs.253682DOI Listing
February 2021

Alternative mitochondrial quality control mediated by extracellular release.

Autophagy 2021 10 10;17(10):2962-2974. Epub 2020 Dec 10.

Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan.

Mitochondrial quality control, which is crucial for maintaining cellular homeostasis, has been considered to be achieved exclusively through mitophagy. Here we report an alternative mitochondrial quality control pathway mediated by extracellular mitochondria release. By performing time-lapse confocal imaging on a stable cell line with fluorescent-labeled mitochondria, we observed release of mitochondria from cells into the extracellular space. Correlative light-electron microscopy revealed that majority of the extracellular mitochondria are in free form and, on rare occasions, some are enclosed in membrane-surrounded vesicles. Rotenone- and carbonyl cyanide m-chlorophenylhydrazone-induced mitochondrial quality impairment promotes the extracellular release of depolarized mitochondria. Overexpression of PRKN (parkin RBR E3 ubiquitin protein ligase), which has a pivotal role in mitophagy regulation, suppresses the extracellular mitochondria release under basal and stress condition, whereas its knockdown exacerbates it. Correspondingly, overexpression of PRKN-independent mitophagy regulators, BNIP3 (BCL2 interacting protein 3) and BNIP3L/NIX (BCL2 interacting protein 3 like), suppress extracellular mitochondria release. Autophagy-deficient cell lines show elevated extracellular mitochondria release. These results imply that perturbation of mitophagy pathway prompts mitochondria expulsion. Presence of mitochondrial protein can also be detected in mouse sera. Sera of PRKN-deficient mice contain higher level of mitochondrial protein compared to that of wild-type mice. More importantly, fibroblasts and cerebrospinal fluid samples from Parkinson disease patients carrying loss-of-function mutations show increased extracellular mitochondria compared to control subjects, providing evidence in a clinical context. Taken together, our findings suggest that extracellular mitochondria release is a comparable yet distinct quality control pathway from conventional mitophagy. ACTB: actin beta; ANXA5: annexin A5; ATP5F1A/ATP5A: ATP synthase F1 subunit alpha; ATG: autophagy related; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CM: conditioned media; CSF: cerebrospinal fluid; DMSO: dimethyl sulfoxide; EM: electron microscopy; HSPD1/Hsp60: heat shock protein family D (Hsp60) member 1; KD: knockdown; KO: knockout; MAP1LC3A/LC3: microtubule associated protein 1 light chain 3 alpha; MT-CO1: mitochondrially encoded cytochrome c oxidase I; NDUFB8: NADH:ubiquinone oxidoreductase subunit B8; OE: overexpression; OPA1: OPA1 mitochondrial dynamin like GTPase; OXPHOS: oxidative phosphorylation; PBS: phosphate-buffered saline; PB: phosphate buffer; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SDHB: succinate dehydrogenase complex iron sulfur subunit B; TOMM20: translocase of outer mitochondrial membrane 20; TOMM40: translocase of outer mitochondrial membrane 40; UQCRC2: ubiquinol-cytochrome c reductase core protein 2; WT: wild-type.
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http://dx.doi.org/10.1080/15548627.2020.1848130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525996PMC
October 2021

Autophagy-independent function of lipidated LC3 essential for TFEB activation during the lysosomal damage responses.

Autophagy 2021 02 13;17(2):581-583. Epub 2020 Nov 13.

Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.

Lysosomes are digestive organelles in cells containing many hydrolases, and also serve as a signaling hub to integrate intracellular and extracellular inputs; therefore, the integrity of lysosomes is critical for cellular homeostasis. Many agents and conditions can damage lysosomal membranes, which lead to leakage of lysosomal acidic contents into the cytosol thus becoming harmful for cells. Accordingly, cells have developed several defense systems to cope with damaged lysosomes, but underlying mechanisms of each system and their cross-talks are unclear. In our recent study, we found that a master transcription factor regulating autophagy and lysosomal biogenesis, TFEB (transcription factor EB) is activated during lysosomal damage, and this activation depends on an autophagy-independent function of lipidated LC3, which localizes on lysosomes. We further showed that this regulatory mechanism is essential to prevent the progression of the crystal nephropathy that accompanies lysosomal damage.
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http://dx.doi.org/10.1080/15548627.2020.1846292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007146PMC
February 2021

LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury.

Nat Cell Biol 2020 10 28;22(10):1252-1263. Epub 2020 Sep 28.

Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.

Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)-a master transcriptional regulator of lysosomal biogenesis and autophagy-is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.
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http://dx.doi.org/10.1038/s41556-020-00583-9DOI Listing
October 2020

Age-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy.

Nat Commun 2020 08 18;11(1):4150. Epub 2020 Aug 18.

Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.

The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.
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http://dx.doi.org/10.1038/s41467-020-17985-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434891PMC
August 2020

Autophagy Declines with Premature Skin Aging resulting in Dynamic Alterations in Skin Pigmentation and Epidermal Differentiation.

Int J Mol Sci 2020 Aug 9;21(16). Epub 2020 Aug 9.

Department of Genetics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.

Autophagy is a membrane traffic system that provides sustainable degradation of cellular components for homeostasis, and is thus considered to promote health and longevity, though its activity declines with aging. The present findings show deterioration of autophagy in association with premature skin aging. Autophagy flux was successfully determined in skin tissues, which demonstrated significantly decreased autophagy in hyperpigmented skin such as that seen in senile lentigo. Furthermore, an exacerbated decline in autophagy was confirmed in xerotic hyperpigmentation areas, accompanied by severe dehydration and a barrier defect, which showed correlations with skin physiological conditions. The enhancement of autophagy in skin ex vivo ameliorated skin integrity, including pigmentation and epidermal differentiation. The present results indicate that the restoration of autophagy can contribute to improving premature skin aging by various intrinsic and extrinsic factors via the normalization of protein homeostasis.
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http://dx.doi.org/10.3390/ijms21165708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460956PMC
August 2020

Rubicon in pancreatic beta cells plays a limited role in maintaining glucose homeostasis following increased insulin resistance.

Endocr J 2020 Nov 16;67(11):1119-1126. Epub 2020 Jul 16.

Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.

Autophagy has been reported to play a crucial role in the maintenance of intracellular homeostasis, including in pancreatic beta cells. Rubicon, which interacts with the phosphoinositide 3-kinase (PI3K) complex, through autophagy-related 14 (ATG14), is among the few autophagy regulators that have been reported to inhibit autophagic flux to date and the deletion of Rubicon has been shown to increase autophagic flux. Based on previous results showing a causal relationship between autophagic dysfunction and pancreatic beta-cell impairment, we hypothesized that the deletion of Rubicon in pancreatic beta cells would improve cell integrity and confer protective effects. To test this hypothesis, we first confirmed that Rubicon knockdown (KD) promoted autophagic flux in βTC3 pancreatic beta-cell line. Next, we generated pancreatic beta-cell-specific Rubicon knockout (βKO) mice, by administering tamoxifen to Rubicon:MIP-Cre-ERT mice, which showed normal glucose tolerance and insulin secretion under a normal chow diet, despite successful gene recombination. We also attempted to increase insulin resistance by feeding the mice with a high-fat diet for an additional 2 months to find little differences among the parameters evaluated for glucose metabolism. Finally, severe insulin resistance was induced with insulin receptor antagonist treatment, which resulted in comparable glucose homeostasis measurements between Rubicon βKO and control mice. In summary, these results suggest that in pancreatic beta cells, Rubicon plays a limited role in the maintenance of systemic glucose homeostasis.
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http://dx.doi.org/10.1507/endocrj.EJ20-0326DOI Listing
November 2020

Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex.

Proc Natl Acad Sci U S A 2020 07 6;117(29):17003-17010. Epub 2020 Jul 6.

Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720;

Rubicon is a potent negative regulator of autophagy and a potential target for autophagy-inducing therapeutics. Rubicon-mediated inhibition of autophagy requires the interaction of the C-terminal Rubicon homology (RH) domain of Rubicon with Rab7-GTP. Here we report the 2.8-Å crystal structure of the Rubicon RH domain in complex with Rab7-GTP. Our structure reveals a fold for the RH domain built around four zinc clusters. The switch regions of Rab7 insert into pockets on the surface of the RH domain in a mode that is distinct from those of other Rab-effector complexes. Rubicon residues at the dimer interface are required for Rubicon and Rab7 to colocalize in living cells. Mutation of Rubicon RH residues in the Rab7-binding site restores efficient autophagic flux in the presence of overexpressed Rubicon, validating the Rubicon RH domain as a promising therapeutic target.
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http://dx.doi.org/10.1073/pnas.2008030117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382272PMC
July 2020

Autophagosome biogenesis and human health.

Cell Discov 2020 2;6(1):33. Epub 2020 Jun 2.

Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, 565-0871 Japan.

Autophagy degrades the cytoplasmic contents engulfed by autophagosomes. Besides providing energy and building blocks during starvation via random degradation, autophagy selectively targets cytotoxic components to prevent a wide range of diseases. This preventive activity of autophagy is supported by many studies using animal models and reports identifying several mutations in autophagy-related genes that are associated with human genetic disorders, which have been published in the past decade. Here, we summarize the molecular mechanisms of autophagosome biogenesis involving the proteins responsible for these genetic disorders, demonstrating a role for autophagy in human health. These findings will help elucidate the underlying mechanisms of autophagy-related diseases and develop future medications.
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http://dx.doi.org/10.1038/s41421-020-0166-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264243PMC
June 2020

ERdj8 governs the size of autophagosomes during the formation process.

J Cell Biol 2020 08;219(8)

Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto, Japan.

In macroautophagy, membrane structures called autophagosomes engulf substrates and deliver them for lysosomal degradation. Autophagosomes enwrap a variety of targets with diverse sizes, from portions of cytosol to larger organelles. However, the mechanism by which autophagosome size is controlled remains elusive. We characterized a novel ER membrane protein, ERdj8, in mammalian cells. ERdj8 localizes to a meshwork-like ER subdomain along with phosphatidylinositol synthase (PIS) and autophagy-related (Atg) proteins. ERdj8 overexpression extended the size of the autophagosome through its DnaJ and TRX domains. ERdj8 ablation resulted in a defect in engulfing larger targets. C. elegans, in which the ERdj8 orthologue dnj-8 was knocked down, could perform autophagy on smaller mitochondria derived from the paternal lineage but not the somatic mitochondria. Thus, ERdj8 may play a critical role in autophagosome formation by providing the capacity to target substrates of diverse sizes for degradation.
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http://dx.doi.org/10.1083/jcb.201903127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401821PMC
August 2020

A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells.

Nat Commun 2020 04 22;11(1):1935. Epub 2020 Apr 22.

Research Institute for Microbial Diseases (RIMD), Osaka University, Suita, 565-0871, Japan.

Although cellular senescence acts primarily as a tumour suppression mechanism, the accumulation of senescent cells in vivo eventually exerts deleterious side effects through inflammatory/tumour-promoting factor secretion. Thus, the development of new drugs that cause the specific elimination of senescent cells, termed senolysis, is anticipated. Here, by an unbiased high-throughput screening of chemical compounds and a bio-functional analysis, we identify BET family protein degrader (BETd) as a promising senolytic drug. BETd provokes senolysis through two independent but integrated pathways; the attenuation of non-homologous end joining (NHEJ), and the up-regulation of autophagic gene expression. BETd treatment eliminates senescent hepatic stellate cells in obese mouse livers, accompanied by the reduction of liver cancer development. Furthermore, the elimination of chemotherapy-induced senescent cells by BETd increases the efficacy of chemotherapy against xenograft tumours in immunocompromised mice. These results reveal the vulnerability of senescent cells and open up possibilities for its control.
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http://dx.doi.org/10.1038/s41467-020-15719-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176673PMC
April 2020

Starvation-induced autophagy via calcium-dependent TFEB dephosphorylation is suppressed by Shigyakusan.

PLoS One 2020 5;15(3):e0230156. Epub 2020 Mar 5.

Center for Frontier Oral Science, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.

Kampo, a system of traditional Japanese therapy utilizing mixtures of herbal medicine, is widely accepted in the Japanese medical system. Kampo originated from traditional Chinese medicine, and was gradually adopted into a Japanese style. Although its effects on a variety of diseases are appreciated, the underlying mechanisms remain mostly unclear. Using a quantitative tf-LC3 system, we conducted a high-throughput screen of 128 kinds of Kampo to evaluate the effects on autophagy. The results revealed a suppressive effect of Shigyakusan/TJ-35 on autophagic activity. TJ-35 specifically suppressed dephosphorylation of ULK1 and TFEB, among several TORC1 substrates, in response to nutrient deprivation. TFEB was dephosphorylated by calcineurin in a Ca2+ dependent manner. Cytosolic Ca2+ concentration was increased in response to nutrient starvation, and TJ-35 suppressed this increase. Thus, TJ-35 prevents the starvation-induced Ca2+ increase, thereby suppressing induction of autophagy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230156PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058311PMC
June 2020

Metabolic effects of RUBCN/Rubicon deficiency in kidney proximal tubular epithelial cells.

Autophagy 2020 10 16;16(10):1889-1904. Epub 2020 Jan 16.

Department of Nephrology, Osaka University Graduate School of Medicine , Osaka, Japan.

Macroautophagy/autophagy is a lysosomal degradation system which plays a protective role against kidney injury. RUBCN/Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein) inhibits the fusion of autophagosomes and lysosomes. However, its physiological role in kidney proximal tubular epithelial cells (PTECs) remains uncertain. In the current study, we analyzed the phenotype of newly generated PTEC-specific -deficient (KO) mice. Additionally, we investigated the role of RUBCN in lipid metabolism using isolated -deficient PTECs. Although KO mice exhibited sustained high autophagic flux in PTECs, they were not protected from acute ischemic kidney injury. Unexpectedly, KO mice exhibited hallmark features of metabolic syndrome accompanied by expanded lysosomes containing multi-layered phospholipids in PTECs. RUBCN deficiency in cultured PTECs promoted the mobilization of phospholipids from cellular membranes to lysosomes via enhanced autophagy. Treatment of KO PTECs with oleic acid accelerated fatty acids transfer to mitochondria. Furthermore, KO PTECs promoted massive triglyceride accumulation in hepatocytes (BNL-CL2 cells) co-cultured in transwell, suggesting accelerated fatty acids efflux from the PTECs contributes to the metabolic syndrome in KO mice. This study shows that sustained high autophagic flux by RUBCN deficiency in PTECs leads to metabolic syndrome concomitantly with an accelerated mobilization of phospholipids from cellular membranes to lysosomes. : ABC: ATP binding cassette; ACADM: acyl-CoA dehydrogenase medium chain; ACTB: actin, beta; ATG: autophagy related; AUC: area under the curve; Baf: bafilomycin A; BAT: brown adipose tissue; BODIPY: boron-dipyrromethene; BSA: bovine serum albumin; BW: body weight; CAT: chloramphenicol acetyltransferase; CM: complete medium; CPT1A: carnitine palmitoyltransferase 1a, liver; CQ: chloroquine; CTRL: control; EGFP: enhanced green fluorescent protein; CTSD: cathepsin D; EAT: epididymal adipose tissue; EGFR: epidermal growth factor receptor; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FA: fatty acid; FBS: fetal bovine serum; GTT: glucose tolerance test; HE: hematoxylin and eosin; HFD: high-fat diet; I/R: ischemia-reperfusion; ITT: insulin tolerance test; KAP: kidney androgen regulated protein; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LD: lipid droplet; LRP2: low density lipoprotein receptor related protein 2; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MAT: mesenteric adipose tissue; MS: mass spectrometry; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NDRG1: N-myc downstream regulated 1; NDUFB5: NADH:ubiquinone oxidoreductase subunit B5; NEFA: non-esterified fatty acid; OA: oleic acid; OCT: optimal cutting temperature; ORO: Oil Red O; PAS: Periodic-acid Schiff; PFA: paraformaldehyde; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PPARA: peroxisome proliferator activated receptor alpha; PPARGC1A: PPARG coactivator 1 alpha; PTEC: proximal tubular epithelial cell; RAB7A: RAB7A, member RAS oncogene family; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RT: reverse transcription; RUBCN: rubicon autophagy regulator; SAT: subcutaneous adipose tissue; SFC: supercritical fluid chromatography; SQSTM1: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1; SV-40: simian virus-40; TFEB: transcription factor EB; TG: triglyceride; TS: tissue specific; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; UN: urea nitrogen; UQCRB: ubiquinol-cytochrome c reductase binding protein; UVRAG: UV radiation resistance associated; VPS: vacuolar protein sorting; WAT: white adipose tissue.
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http://dx.doi.org/10.1080/15548627.2020.1712107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386605PMC
October 2020

Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia.

Autophagy 2020 10 26;16(10):1771-1785. Epub 2019 Dec 26.

Departments of Pediatrics, Obstetrics and Gynecology and Pathology, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University , Providence, RI, USA.

The etiology of preeclampsia (PE), a serious pregnancy complication, remains an enigma. We have demonstrated that proteinopathy, a pathologic feature of neurodegenerative diseases, is a key observation in the placenta and serum from PE patients. We hypothesize that the macroautophagy/autophagy machinery that mediates degradation of aggregated proteins and damaged organelles is impaired in PE. Here, we show that TFEB (transcription factor EB), a master transcriptional regulator of lysosomal biogenesis, and its regulated proteins, LAMP1, LAMP2, and CTSD (cathepsin D), were dysregulated in the placenta from early and late onset PE deliveries. Primary human trophoblasts and immortalized extravillous trophoblasts (EVTs) showed reduced TFEB expression and nuclear translocation as well as lysosomal protein content in response to hypoxia. Hypoxia-exposed trophoblasts also showed decreased PPP3/calcineurin phosphatase activity and increased XPO1/CRM1 (exportin 1), events that inhibit TFEB nuclear translocation. These proteins were also dysregulated in the PE placenta. These results are supported by observed lysosomal ultrastructural defects with decreased number of autolysosomes in hypoxia-treated primary human trophoblasts. Autophagy-deficient human EVTs exhibited poor TFEB nuclear translocation, reduced lysosomal protein expression and function, and increased MTORC1 activity. Sera from PE patients induced these features and protein aggregation in EVTs. Importantly, trophoblast-specific conditional knockout mice exhibited reduced TFEB expression with increased deposition of protein aggregates in the placenta. These results provide compelling evidence for a regulatory link between accumulation of protein aggregates and TFEB-mediated impaired lysosomal biogenesis and autophagy in the placenta of PE patients. : autophagy related 7; CTSD: cathepsin D; ER: endoplasmic reticulum; EVTs: extravillous trophoblasts; KRT7: keratin 7; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; mSt: mStrawberry; MTORC1: mechanistic target of rapamycin complex 1; NP: normal pregnancy; NPS: normal pregnancy serum; PE: preeclampsia; PES: preeclampsia serum; p-RPS6KB: phosphorylated ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; XPO1/CRM1: exportin 1.
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http://dx.doi.org/10.1080/15548627.2019.1707494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386603PMC
October 2020

Autophagy-activating strategies to promote innate defense against mycobacteria.

Exp Mol Med 2019 12 11;51(12):1-10. Epub 2019 Dec 11.

Department of Microbiology, Chungnam National University School of Medicine, Daejeon, 35015, Korea.

Mycobacterium tuberculosis (Mtb) is a major causal pathogen of human tuberculosis (TB), which is a serious health burden worldwide. The demand for the development of an innovative therapeutic strategy to treat TB is high due to drug-resistant forms of TB. Autophagy is a cell-autonomous host defense mechanism by which intracytoplasmic cargos can be delivered and then destroyed in lysosomes. Previous studies have reported that autophagy-activating agents and small molecules may be beneficial in restricting intracellular Mtb infection, even with multidrug-resistant Mtb strains. Recent studies have revealed the essential roles of host nuclear receptors (NRs) in the activation of the host defense through antibacterial autophagy against Mtb infection. In particular, we discuss the function of estrogen-related receptor (ERR) α and peroxisome proliferator-activated receptor (PPAR) α in autophagy regulation to improve host defenses against Mtb infection. Despite promising findings relating to the antitubercular effects of various agents, our understanding of the molecular mechanism by which autophagy-activating agents suppress intracellular Mtb in vitro and in vivo is lacking. An improved understanding of the antibacterial autophagic mechanisms in the innate host defense will eventually lead to the development of new therapeutic strategies for human TB.
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http://dx.doi.org/10.1038/s12276-019-0290-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906292PMC
December 2019

Deregulated MTOR (mechanistic target of rapamycin kinase) is responsible for autophagy defects exacerbating kidney stone development.

Autophagy 2020 04 29;16(4):709-723. Epub 2019 Jun 29.

Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan.

Kidney stone disease is a lifestyle-related disease prevalent in developed countries; however, effective medical treatment for the disease is not yet well established. As cellular damage in renal tubular cells (RTCs) is responsible for the disease, here, we focused on the role of macroautophagy/autophagy in RTCs. We found that autophagic activity was significantly decreased in mouse RTCs exposed to calcium oxalate (CaOx) monohydrate crystals and in the kidneys of GFP-conjugated MAP1LC3B (microtubule- associated protein 1 light chain 3 beta) transgenic mice with CaOx nephrocalcinosis induced by glyoxylate. This caused accumulation of damaged intracellular organelles, such as mitochondria and lysosomes, the normal functioning of which is mediated by functional autophagy. An impairment of autophagy was also observed in the mucosa with plaques of CaOx kidney stone formers. We determined that the decrease in autophagy was caused by an upregulation of MTOR (mechanistic target of rapamycin kinase), which consequently resulted in the suppression of the upstream autophagy regulator TFEB (transcription factor EB). Furthermore, we showed that an MTOR inhibitor could recover a decrease in autophagy and alleviate crystal-cell interactions and the formation of crystals associated with increased inflammatory responses. Taken together, we conclude that autophagy compromised by MTOR deregulation is a fundamental feature in the pathology of kidney stone formation, and propose that chemical inhibition of MTOR could be a prospective strategy for disease suppression.: ACTB: actin, beta; CaOx: calcium oxalate; CKD: chronic kidney disease; COM: calcium oxalate monohydrate; LGALS3/galectin-3: lectin, galactose binding, soluble 3; GFP: green fluorescent protein; GOX: glyoxylate; HE: hematoxylin and eosin; MAPLC3B: microtubule- associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; ROS: reactive oxygen species; RTC: renal tubular cell; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TEM: transmission electron microscopy; tfLC3: tandem fluorescent-tagged LC3; 3-MA: 3-methyladenine.
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http://dx.doi.org/10.1080/15548627.2019.1635382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138204PMC
April 2020

Autophagy, Inflammation, and Metabolism (AIM) Center in its second year.

Autophagy 2019 10 15;15(10):1829-1833. Epub 2019 Jul 15.

Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo , Tokyo , Japan.

The NIH-funded center for autophagy research named Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence, located at the University of New Mexico Health Science Center is now completing its second year as a working center with a mission to promote autophagy research locally, nationally, and internationally. The center has thus far supported a cadre of 6 junior faculty (mentored PIs; mPIs) at a near-R01 level of funding. Two mPIs have graduated by obtaining their independent R01 funding and 3 of the remaining 4 have won significant funding from NIH in the form of R21 and R56 awards. The first year and a half of setting up the center has been punctuated by completion of renovations and acquisition and upgrades for equipment supporting autophagy, inflammation and metabolism studies. The scientific cores usage, and the growth of new studies is promoted through pilot grants and several types of enablement initiatives. The intent to cultivate AIM as a scholarly hub for autophagy and related studies is manifested in its Vibrant Campus Initiative, and the Tuesday AIM Seminar series, as well as by hosting a major scientific event, the 2019 AIM symposium, with nearly one third of the faculty from the International Council of Affiliate Members being present and leading sessions, giving talks, and conducting workshop activities. These and other events are often videostreamed for a worldwide scientific audience, and information about events at AIM and elsewhere are disseminated on Twitter and can be followed on the AIM web site. AIM intends to invigorate research on overlapping areas between autophagy, inflammation and metabolism with a number of new initiatives to promote metabolomic research. With the turnover of mPIs as they obtain their independent funding, new junior faculty are recruited and appointed as mPIs. All these activities are in keeping with AIM's intention to enable the next generation of autophagy researchers and help anchor, disseminate, and convey the depth and excitement of the autophagy field.
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http://dx.doi.org/10.1080/15548627.2019.1634444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735631PMC
October 2019

Suppression of autophagic activity by Rubicon is a signature of aging.

Nat Commun 2019 02 19;10(1):847. Epub 2019 Feb 19.

Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.

Autophagy, an evolutionarily conserved cytoplasmic degradation system, has been implicated as a convergent mechanism in various longevity pathways. Autophagic activity decreases with age in several organisms, but the underlying mechanism is unclear. Here, we show that the expression of Rubicon, a negative regulator of autophagy, increases in aged worm, fly and mouse tissues at transcript and/or protein levels, suggesting that an age-dependent increase in Rubicon impairs autophagy over time, and thereby curtails animal healthspan. Consistent with this idea, knockdown of Rubicon extends worm and fly lifespan and ameliorates several age-associated phenotypes. Tissue-specific experiments reveal that Rubicon knockdown in neurons has the greatest effect on lifespan. Rubicon knockout mice exhibits reductions in interstitial fibrosis in kidney and reduced α-synuclein accumulation in the brain. Rubicon is suppressed in several long-lived worms and calorie restricted mice. Taken together, our results suggest that suppression of autophagic activity by Rubicon is one of signatures of aging.
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http://dx.doi.org/10.1038/s41467-019-08729-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381146PMC
February 2019
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