Publications by authors named "Chengyu Liang"

72 Publications

Bacterial community compositions and nitrogen metabolism function in a cattle farm wastewater treatment plant revealed by Illumina high-throughput sequencing.

Environ Sci Pollut Res Int 2021 Aug 26;28(30):40895-40907. Epub 2021 Mar 26.

Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China.

Bacteria play an important role in pollutant transformation in activated sludge-based wastewater treatment plants (WWTPs). Exploring the microbial community structure and diversity is essential to improving the performance of wastewater treatment processes. This study employed Illumina MiSeq high-throughput sequencing to investigate the microbial community composition and diversity in a cattle farm wastewater treatment plant (Cf-WWTP). The results showed that the dominant phyla in the whole process were Proteobacteria, Bacteroidetes, and Firmicutes. The principal coordinate analysis (PCoA) indicated that the different stages had a significant impact on the microbial community structure; Bacteroidetes was the dominant phylum in the anearobic stage and Proteobacteria was the dominant phylum in the anoxic-oxic stage. Redundancy analysis (RDA) revealed that total phosphorus (TP) was the most significant factor that regulated the microbial community composition, followed by chemical oxygen demand (COD), total nitrogen (TN), and pH. Proteobacteria, Patescibacteria, and Chloroflexi were simultaneously negatively correlated with TN, COD, and TP. Nitrogen metabolic pathway and transformation mechanism was elucidated by a complete denitrification function predicted with phylogenetic investigation of communities with reconstruction of unobserved states (PICRUSt), as well as detection of ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB). These results provide new insights into our understanding of microbial community and metabolic functions of Cf-WWTP.
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http://dx.doi.org/10.1007/s11356-021-13570-wDOI Listing
August 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

Intrinsic Semiconducting Behavior in a Large Mixed-Valent Uranium(V/VI) Cluster.

Angew Chem Int Ed Engl 2021 Apr 18;60(18):9886-9890. Epub 2021 Mar 18.

State Key Laboratory of Radiation Medicine and Protection, School for Radiological and interdisciplinary Sciences (RAD-X) and Collaborative Innovation Center of Radiation Medicine of, Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China.

We disclose the intrinsic semiconducting properties of one of the largest mixed-valent uranium clusters, [H O ][U (U O ) (μ -O) (PhCOO) (Py(CH O) ) (DMF) ] (Ph=phenyl, Py=pyridyl, DMF=N,N-dimethylformamide) (1). Single-crystal X-ray crystallography demonstrates that U center is stabilized within a tetraoxo core surrounded by eight uranyl(VI) pentagonal bipyramidal centers. The oxidation states of uranium are substantiated by spectroscopic data and magnetic susceptibility measurement. Electronic spectroscopy and theory corroborate that U species serve as electron donors and thus facilitate 1 being a n-type semiconductor. With the largest effective atomic number among all reported radiation-detection semiconductor materials, charge transport properties and photoconductivity were investigated under X-ray excitation for 1: a large on-off ratio of 500 and considerable charge mobility lifetime product of 2.3×10  cm  V , as well as a high detection sensitivity of 23.4 μC Gy  cm .
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http://dx.doi.org/10.1002/anie.202017298DOI Listing
April 2021

Removal of antibiotic resistance genes from swine wastewater by membrane filtration treatment.

Ecotoxicol Environ Saf 2021 Mar 8;210:111885. Epub 2021 Jan 8.

Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China; Shanghai Engineering Research Center of Biotransformation of Organic Solid Waste, Shanghai 200241, China. Electronic address:

Antibiotic resistance genes (ARGs) have attracted extensive attention as an emerging environmental contaminant potentially threatening humans. One of the main emission sources of ARGs is swine wastewater. In this study, integrated membrane filtration including ultrafiltration and two-stage reverse osmosis was conducted for swine wastewater treatment. The abundances of 16 target ARGs, which accounted for 72.64% of the total ARGs in swine wastewater according to metagenomic sequencing, were quantified by quantitative real-time PCR (qPCR) during each stage of the membrane filtration process. The results showed that integrated membrane filtration could reduce more than 99.0% of conventional pollutants and 99.79% of ARGs (from 3.02 × 10 copy numbers/mL to 6.45 × 10 copy numbers/mL). Principal component analysis (PCA) indicated that the removal efficiency of ARGs subtype by membrane filtration did not depend on ARGs type. However, strong correlations were found between ARGs and the wastewater quality indicators TP, SS and EC according to Cooccurrence patterns, indicating that ARG removal was closely associated with insoluble solid particles and soluble ions in swine wastewater. These results showed that membrane filtration could not only remove conventional pollutants such as nitrogen and phosphorus but also reduce the emerging pollutant of ARGs and decrease the risk of ARGs flowing into natural water.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111885DOI Listing
March 2021

Three-Dimensional Polycatenation of a Uranium-Based Metal-Organic Cage: Structural Complexity and Radiation Detection.

J Am Chem Soc 2020 Sep 9;142(38):16218-16222. Epub 2020 Sep 9.

State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.

The potential applications of metal-organic cages (MOCs) are mostly achieved through specific host-guest interactions within their cavities. Electronic applications would require an effective electron transport pathway, which has been extensively studied in hybrid organic-inorganic materials with extended structures. These properties have not been considered for MOCs because cage-to-cage interactions in these materials have rarely been examined and are challenging to functionalize. We report here a previously unobserved actinide-based MOC assembled from four hexagonal-bipyramidal-coordinated uranyl ions and six bidentate flexible ligands. Remarkably, each isolated cage is further interlocked with six adjacent ones through mechanical bonds, resulting in the first case of a 0D → 3D f-element polycatenated metal-organic cage, . Long-range π-π stacking extending throughout the structure is built via polycatenation, providing a visible carrier transmission path. is also an extremely rare case of an intrinsically semiconductive MOC with a wide band gap of 2.61 eV. Combined with the high X-ray attenuation efficiency, can effectively convert X-ray photons to electrical current signals and presents a promising sensitivity of 54.93 μC Gy cm.
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http://dx.doi.org/10.1021/jacs.0c08117DOI Listing
September 2020

A Photoconductive X-ray Detector with a High Figure of Merit Based on an Open-Framework Chalcogenide Semiconductor.

Angew Chem Int Ed Engl 2020 Oct 11;59(42):18605-18610. Epub 2020 Sep 11.

College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, Jiangsu, 215123, China.

A wide range of tunability in the physical parameters of a semiconductor used for X-ray detection is desirable to achieve targeted performance optimization. However, in a dense-phase semiconductor, fine-tuning one parameter often leads to unwanted changes in other parameters. Herein, the intrinsic openness in an open-framework semiconductor has been confirmed, for the first time, to be a key structural factor that weakens the mutual exclusivity of the adjustable physical parameters owing to a non-linear control mechanism. The controllable doping of S in a zeolitic In-Se host results in an optimal balance between resistivity, band gap, and carrier mobility, which finally results in an excellent X-ray detector with a high figure of merit for the mobility-lifetime product (7.12×10  cm  V ); this value is superior to that of a commercial α-Se detector. The current strategy of choosing open-framework semiconductor materials opens a new window for targeting high-performance X-ray detection.
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http://dx.doi.org/10.1002/anie.202010290DOI Listing
October 2020

p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs.

Nat Commun 2020 06 17;11(1):3084. Epub 2020 Jun 17.

Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, 90033, USA.

Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Cell-fate-determinant molecule NUMB-interacting protein (TBC1D15) is overexpressed and contributes to p53 degradation in TICs. Here we identify TBC1D15-mediated oncogenic mechanisms and tested the tumorigenic roles of TBC1D15 in vivo. We examined hepatocellular carcinoma (HCC) development in alcohol Western diet-fed hepatitis C virus NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or expression of non-phosphorylatable NUMB mutations. Liver-specific TBC1D15 deficiency or non-p-NUMB expression reduced TIC numbers and HCC development. TBC1D15-NuMA1 association impaired asymmetric division machinery by hijacking NuMA from LGN binding, thereby favoring TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 which upregulated transcription of NANOG essential for TIC expansion. TBC1D15 activated three novel oncogenic pathways to promote self-renewal, p53 loss, and Nanog transcription in TICs. Thus, this central regulator could serve as a potential therapeutic target for treatment of HCC.
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http://dx.doi.org/10.1038/s41467-020-16616-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299990PMC
June 2020

Thermoplastic Membranes Incorporating Semiconductive Metal-Organic Frameworks: An Advance on Flexible X-ray Detectors.

Angew Chem Int Ed Engl 2020 Jul 11;59(29):11856-11860. Epub 2020 May 11.

State Key Laboratory of Radiation Medicine and Protection, School for Radiological and interdisciplinary Sciences (RAD-X) and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China.

Semiconductive metal-organic frameworks (MOFs) have emerged in applications such as chemical sensors, electrocatalysts, energy storage materials, and electronic devices. However, examples of semiconductive MOFs within flexible electronics have not been reported. We present flexible X-ray detectors prepared by thermoplastic dispersal of a semiconductive MOF (SCU-13) through a commercially available polymer, poly(vinylidene fluoride). The flexible detectors exhibit efficient X-ray-to-electric current conversion with enhanced charge-carrier mobility and low trap density compared to pelleted devices. A high X-ray detection sensitivity of 65.86 μCGy  cm was achieved, which outperforms other pelleted devices and commercial flexible X-ray detectors. We demonstrate that the MOF-based flexible detectors can be operated at multiple bending angles without a deterioration in detection performance. As a proof-of-concept, an X-ray phase contrast under bending conditions was constructed using a 5×5 pixelated MOF-based imager.
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http://dx.doi.org/10.1002/anie.202004006DOI Listing
July 2020

How autophagy is tied to inflammation and cancer.

Mol Cell Oncol 2020 4;7(2):1717908. Epub 2020 Feb 4.

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

It is not completely understood how autophagy is tied to inflammation and age-related cancer predisposition. Here, we used a mouse model with inducible expression of a cancer-derived frameshift mutation in ) to demonstrate that intervention with autophagy suppressor could exacerbate inflammation and promote age-related spontaneous cancers.
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http://dx.doi.org/10.1080/23723556.2020.1717908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051155PMC
February 2020

HIV-1 Nef counteracts autophagy restriction by enhancing the association between BECN1 and its inhibitor BCL2 in a PRKN-dependent manner.

Autophagy 2021 02 25;17(2):553-577. Epub 2020 Feb 25.

Biological Sciences, College of Arts and Sciences, Texas Tech University, Lubbock, TX, USA.

Macroautophagy/autophagy is an auto-digestive pro-survival pathway activated in response to stress to target cargo for lysosomal degradation. In recent years, autophagy has become prominent as an innate antiviral defense mechanism through multiple processes, such as targeting virions and viral components for elimination. These exciting findings have encouraged studies on the ability of autophagy to restrict HIV. However, the role of autophagy in HIV infection remains unclear. Whereas some reports indicate that autophagy is detrimental for HIV, others have claimed that HIV deliberately activates this pathway to increase its infectivity. Moreover, these contrasting findings seem to depend on the cell type investigated. Here, we show that autophagy poses a hurdle for HIV replication, significantly reducing virion production. However, HIV-1 uses its accessory protein Nef to counteract this restriction. Previous studies have indicated that Nef affects autophagy maturation by preventing the fusion between autophagosomes and lysosomes. Here, we uncover that Nef additionally blocks autophagy initiation by enhancing the association between BECN1 and its inhibitor BCL2, and this activity depends on the cellular E3 ligase PRKN. Remarkably, the ability of Nef to counteract the autophagy block is more frequently observed in pandemic HIV-1 and its simian precursor SIV infecting chimpanzees than in HIV-2 and its precursor SIV infecting sooty mangabeys. In summary, our findings demonstrate that HIV-1 is susceptible to autophagy restriction and define Nef as the primary autophagy antagonist of this antiviral process. 3-MA: 3-methyladenine; ACTB: actin, beta; ATG16L1: autophagy related 16 like 1; BCL2: bcl2 apoptosis regulator; BECN1: beclin 1; cDNA: complementary DNA; EGFP: enhanced green fluorescence protein; ER: endoplasmic reticulum; Gag/p55: group-specific antigen; GFP: green fluorescence protein; GST: glutathione S transferase; HA: hemagglutinin; HIV: human immunodeficiency virus; IP: immunoprecipitation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nef: negative factor; PRKN: parkin RBR E3 ubiquitin ligase; PtdIns3K: phosphatidylinositol 3 kinase; PtdIns3P: phosphatidylinositol 3 phosphate; PTM: post-translational modification; RT-qPCR: reverse transcription followed by quantitative PCR; RUBCN: rubicon autophagy regulator; SEM: standard error of the mean; SERINC3: serine incorporator 3; SERINC5: serine incorporator 5; SIV: simian immunodeficiency virus; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; UVRAG: UV radiation resistance associated gene; VSV: vesicular stomatitis virus; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.
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http://dx.doi.org/10.1080/15548627.2020.1725401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007141PMC
February 2021

UVRAG in autophagy, inflammation, and cancer.

Autophagy 2020 02 7;16(2):387-388. Epub 2020 Jan 7.

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Macroautophagy/autophagy deregulation has been observed in perpetuated inflammation and the proliferation of tumor cells. However, the mechanisms underlying these changes have yet to be well-identified. UVRAG is one of the key players of autophagy, but its role in vivo remained puzzling. Our recent study utilized a mouse model with inducible expression of a cancer-derived frameshift (FS) mutation in that dominant-negatively inhibits wild-type UVRAG, resulting in impaired stimulus-induced autophagy. The systemically compromised autophagy, particularly mitophagy, notably increases inflammation and associated pathologies. Furthermore, our discovery indicates that time-dependent autophagy suppression and ensuing CTNNB1/β-catenin activation may serve as one tumor-promoting mechanism underpinning age-related cancer susceptibility.
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http://dx.doi.org/10.1080/15548627.2019.1709768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984451PMC
February 2020

and mutant mice reveal MTORC1 activation due to impaired lysosomal degradation and exocytosis.

Autophagy 2020 09 26;16(9):1635-1650. Epub 2019 Dec 26.

Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, CA, USA.

How lysosome and MTORC1 signaling interact remains elusive in terminally differentiated cells. A G4C2 repeat expansion in is the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS-FTD). We previously identified a C9orf72-SMCR8-containing complex. Here we found that and double-knockout (dKO) mice exhibit similar but more severe immune defects than the individual . In or mutant macrophages, lysosomal degradation and exocytosis were impaired due to the disruption of autolysosome acidification. As a result of impaired lysosomal degradation, MTOR protein was aberrantly increased, resulting in MTORC1 signaling overactivation. Inhibition of hyperactive MTORC1 partially rescued macrophage dysfunction, splenomegaly and lymphadenopathy in or mutant mice. Pharmacological inhibition of lysosomal degradation upregulated MTOR protein and MTORC1 signaling in differentiated wild-type macrophages, which resemble phenotypes in KO mice. In contrast, or depletion in proliferating macrophages decreased MTORC1 signaling. Our studies causatively link C9orf72-SMCR8's cellular functions in lysosomal degradation, exocytosis, and MTORC1 signaling with their organism-level immune regulation, suggesting cell state (proliferation vs. differentiation)-dependent regulation of MTOR signaling via lysosomes.: ALS: amyotrophic lateral sclerosis; ATG13: autophagy related 13; BMDMs: bone marrow-derived macrophages; BafA: bafilomycin A; C9orf72: C9orf72, member of C9orf72-SMCR8 complex; CD68: CD68 antigen; ConA: concanamycin A; dKO: double knockout; DENN: differentially expressed in normal and neoplastic cells; FTD: frontotemporal dementia; GEF: guanine nucleotide exchange factor; IFNB1: interferon beta 1, fibroblast; IFNG: interferon gamma; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; iPSCs: induced pluripotent stem cells; LAMP1: lysosomal-associated membrane protein 1; LPOs: LAMP1-positive organelles; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; LPS: lipopolysaccharide; MTORC1: mechanistic target of rapamycin kinase complex 1; MEFs: mouse embryonic fibroblasts; MNs: motor neurons; NOS2/iNOS: nitric oxide synthase 2, inducible; RAN: repeat-associated non-AUG; RB1CC1/FIP200: RB1-inducible coiled-coil 1; RPS6/S6: ribosomal protein S6; RPS6KB1/S6K1: ribosomal protein S6 kinase, polypeptide 1; SMCR8: Smith-Magenis syndrome chromosome region, candidate 8; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TNF: tumor necrosis factor; TSC1: TSC complex subunit 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H⁺-translocating ATPase.
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http://dx.doi.org/10.1080/15548627.2019.1703353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386604PMC
September 2020

A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice.

Nat Commun 2019 12 12;10(1):5681. Epub 2019 Dec 12.

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.

Aberrant autophagy is a major risk factor for inflammatory diseases and cancer. However, the genetic basis and underlying mechanisms are less established. UVRAG is a tumor suppressor candidate involved in autophagy, which is truncated in cancers by a frameshift (FS) mutation and expressed as a shortened UVRAG. To investigate the role of UVRAG in vivo, we generated mutant mice that inducibly express UVRAG (iUVRAG). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAG mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAG mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant β-catenin stabilization, and centrosome amplification. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.
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http://dx.doi.org/10.1038/s41467-019-13475-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908726PMC
December 2019

Tumour-Secreted Hsp90α on External Surface of Exosomes Mediates Tumour - Stromal Cell Communication via Autocrine and Paracrine Mechanisms.

Sci Rep 2019 10 22;9(1):15108. Epub 2019 Oct 22.

Department of Dermatology and the USC-Norris Comprehensive Cancer Center, University of Southern California Keck Medical Centre, Los Angeles, CA, 90033, USA.

Extracellular heat shock protein-90alpha (eHsp90α) plays an essential role in tumour invasion and metastasis. The plasma eHsp90α levels in patients with various cancers correlate with the stages of the diseases. Nonetheless, the mechanism of action by tumour-secreted eHsp90α remained unclear. Here we show that eHsp90α accounts for approximately 1% of the total cellular Hsp90α and is associated with tumour-secreted exosomes. CRISPR-cas9 knockout of Hsp90α did not affect the overall distribution and quantity of secreted exosomes, but it caused increased exosome-associated CD9 and decreased exosome-associated TSG101, Alix, and CD63. However, Hsp90α-knockout tumour cells have not only lost their own constitutive motility, but also the ability to recruit stromal cells via secreted exosomes. These defects are specifically due to the lack of eHsp90α on tumour cell-secreted exosomes. Anti-Hsp90α antibody nullified the pro-motility activity of tumour-secreted exosomes and human recombinant Hsp90α protein fully rescued the functional defects of eHsp90α-free exosomes. Finally, while current exosome biogenesis models exclusively implicate the luminal location of host cytosolic proteins inside secreted exosomes, we provide evidence for eHsp90α location on the external surface of tumour-secreted exosomes. Taken together, this study elucidates a new mechanism of action by exosome-associated eHsp90α.
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http://dx.doi.org/10.1038/s41598-019-51704-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805946PMC
October 2019

Photo-exfoliation of a highly photo-responsive two-dimensional metal-organic framework.

Chem Commun (Camb) 2019 Oct 11;55(78):11715-11718. Epub 2019 Sep 11.

School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Jiangsu 215123, China.

When exposed to UV (365 nm, 2 mW) radiation, the bulk crystals of a two-dimensional metal-organic framework [Hphen][(UO)(ox)] (1,phen = 1,10-phenanthroline, ox = oxalate) are exfoliated into thin sheets (2 μm) and its photoluminescence can be quenched in an incredibly sensitive manner, setting 1 as a superior UV-detection material. When upgrading the UV source into a 300 W xenon light source, the crystals of 1 can be further exfoliated into monolayer nanosheets (0.92 nm).
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http://dx.doi.org/10.1039/c9cc05455cDOI Listing
October 2019

Revisiting the role of autophagy in melanoma.

Autophagy 2019 10 29;15(10):1843-1844. Epub 2019 Jun 29.

Department of Molecular Microbiology and Immunology, University of Southern California , Los Angeles , CA , USA.

Although alterations of the macroautophagy/autophagy-lysosome pathway have been observed in cancer for many years, the mechanisms underlying these changes and the importance of autophagic and lysosomal reprogramming by cancer have yet to be well identified. Our recent study demonstrates that oncogenic BRAF signaling promotes melanoma growth and resistance to BRAF-targeted therapy through phosphorylation and functional inactivation of TFEB (transcription factor EB) and consequent suppression of the autophagy-lysosome gene network. This is by no means the first time that this pathway has been directly linked to oncogenic BRAF-driven melanoma. The key observations revealed in this study also leads to a complex but growing convergence of our understanding of the biology of the autophagy-lysosome pathway and the mechanisms underlying cancer prevention and treatment.
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http://dx.doi.org/10.1080/15548627.2019.1635386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735499PMC
October 2019

Transcriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance.

Nat Commun 2019 04 12;10(1):1693. Epub 2019 Apr 12.

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.

Autophagy maintains homeostasis and is induced upon stress. Yet, its mechanistic interaction with oncogenic signaling remains elusive. Here, we show that in BRAF-melanoma, autophagy is induced by BRAF inhibitor (BRAFi), as part of a transcriptional program coordinating lysosome biogenesis/function, mediated by the TFEB transcription factor. TFEB is phosphorylated and thus inactivated by BRAF via its downstream ERK independently of mTORC1. BRAFi disrupts TFEB phosphorylation, allowing its nuclear translocation, which is synergized by increased phosphorylation/inactivation of the ZKSCAN3 transcriptional repressor by JNK2/p38-MAPK. Blockade of BRAFi-induced transcriptional activation of autophagy-lysosomal function in melanoma xenografts causes enhanced tumor progression, EMT-transdifferentiation, metastatic dissemination, and chemoresistance, which is associated with elevated TGF-β levels and enhanced TGF-β signaling. Inhibition of TGF-β signaling restores tumor differentiation and drug responsiveness in melanoma cells. Thus, the "BRAF-TFEB-autophagy-lysosome" axis represents an intrinsic regulatory pathway in BRAF-mutant melanoma, coupling BRAF signaling with TGF-β signaling to drive tumor progression and chemoresistance.
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http://dx.doi.org/10.1038/s41467-019-09634-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461621PMC
April 2019

Nitrogen limitation affects the sinking property of Microcystis by promoting carbohydrate accumulation.

Chemosphere 2019 Apr 11;221:665-671. Epub 2019 Jan 11.

Shanghai Key Lab for Urban Ecological Processes and Eco-Restoration, School of Ecological and Environmental Sciences, East China Normal University, 500 Dong Chuan Road, Shanghai, 200241, PR China; Institute of Eco-Chongming, 3663 N. Zhongshan Road, Shanghai, 200062, PR China. Electronic address:

Nitrogen limitation has been proven to inhibit Microcystis proliferation, and the significant decline in Microcystis blooms in late summer or autumn has been considered to be related to the nitrogen depletion in water. Sinking loss is another factor that influences the dynamics of cyanobacteria in lakes. However, to date, it is still unclear how the sinking property of Microcystis responds to nitrogen availability. Our results suggest that nitrogen limitation would directly influence sinking property of Microcystis, through a significant increase in the specific density of cells. In the short term, carbohydrate accumulation was mainly responsible for the high specific density, showing a high correlation among the NO-N concentration, specific density and carbohydrate content. Furthermore, carbohydrates could rapidly accumulate after one light/dark cycle, which was mainly due to the reduction in carbohydrate consumption in the darkness under nitrogen limitation. Under nitrogen-light coupling conditions, the specific density ranged from 1.060 to 1.068, except for the treatment with high-nitrogen plus low-light, which showed the value of 1.032. More importantly, when coupled with low nitrogen, the low light did not decrease the carbohydrate content and the specific density, which implied that the sinking cells could not migrate back to the surface. Accordingly, a hypothesis was proposed that the carbohydrate accumulation induced by low nitrogen availability caused an increase in specific density, which invalidates the buoyancy regulation, and cells sink continually out of the water column. This study explores a new understanding on the disappearance mechanisms of Microcystis blooms in the late summer and fall.
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http://dx.doi.org/10.1016/j.chemosphere.2019.01.080DOI Listing
April 2019

Darkening with UVRAG.

Autophagy 2019 02 22;15(2):366-367. Epub 2018 Sep 22.

a Department of Molecular Microbiology and Immunology , University of Southern California , Los Angeles , CA , USA.

Ultraviolet radiation (UVR)-induced skin pigmentation, afforded by the dark organelles termed melanosomes, accounts for the first-line protection against environmental UVR that increases the risk of developing skin cancers including melanoma. We have recently discovered that UVRAG, originally identified as a BECN1-binding macroautophagy/autophagy protein, appears to have a specialized function in melanosome biogenesis beyond autophagy through its interaction with the biogenesis of lysosome-related organelles complex 1 (BLOC-1). This melanogenic function of UVRAG is controlled by the melanocyte-specific transcription factor MITF as a downstream effector of the α-melanocyte-stimulating hormone (α-MSH)-cAMP signaling in the suntan response, which is compromised in BRAF mutant melanoma. Thus we propose a new mode of UVRAG activity and regulation in melanocyte biology that may affect melanoma predisposition.
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http://dx.doi.org/10.1080/15548627.2018.1522911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333458PMC
February 2019

Central role of autophagic UVRAG in melanogenesis and the suntan response.

Proc Natl Acad Sci U S A 2018 08 30;115(33):E7728-E7737. Epub 2018 Jul 30.

Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033;

UV-induced cell pigmentation represents an important mechanism against skin cancers. Sun-exposed skin secretes α-MSH, which induces the lineage-specific transcriptional factor MITF and activates melanogenesis in melanocytes. Here, we show that the autophagic tumor suppressor UVRAG plays an integral role in melanogenesis by interaction with the biogenesis of lysosome-related organelles complex 1 (BLOC-1). This interaction is required for BLOC-1 stability and for BLOC-1-mediated cargo sorting and delivery to melanosomes. Absence of UVRAG dispersed BLOC-1 distribution and activity, resulting in impaired melanogenesis in vitro and defective melanocyte development in zebrafish in vivo. Furthermore, our results establish UVRAG as an important effector for melanocytes' response to α-MSH signaling as a direct target of MITF and reveal the molecular basis underlying the association between oncogenic BRAF and compromised UV protection in melanoma.
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http://dx.doi.org/10.1073/pnas.1803303115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099899PMC
August 2018

Novel Role of vBcl2 in the Virion Assembly of Kaposi's Sarcoma-Associated Herpesvirus.

J Virol 2018 02 30;92(4). Epub 2018 Jan 30.

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

The viral Bcl-2 homolog (vBcl2) of Kaposi's sarcoma-associated herpesvirus (KSHV) displays efficient antiapoptotic and antiautophagic activity through its central BH3 domain, which functions to prolong the life span of virus-infected cells and ultimately enhances virus replication and latency. Independent of its antiapoptotic and antiautophagic activity, vBcl2 also plays an essential role in KSHV lytic replication through its amino-terminal amino acids (aa) 11 to 20. Here, we report a novel molecular mechanism of vBcl2-mediated regulation of KSHV lytic replication. vBcl2 specifically bound the tegument protein open reading frame 55 (ORF55) through its amino-terminal aa 11 to 20, allowing their association with virions. Consequently, the vBcl2 peptide derived from vBcl2 aa 11 to 20 effectively disrupted the interaction between vBcl2 and ORF55, inhibiting the incorporation of the ORF55 tegument protein into virions. This study provides new insight into vBcl2's function in KSHV virion assembly that is separable from its inhibitory role in host apoptosis and autophagy. KSHV, an important human pathogen accounting for a large percentage of virally caused cancers worldwide, has evolved a variety of stratagems for evading host immune responses to establish lifelong persistent infection. Upon viral infection, infected cells can go through programmed cell death, including apoptosis and autophagy, which plays an effective role in antiviral responses. To counter the host response, KSHV vBcl2 efficiently blocks apoptosis and autophagy to persist for the life span of virus-infected cells. Besides its anti-programmed-cell-death activity, vBcl2 also interacts with the ORF55 tegument protein for virion assembly in infected cells. Interestingly, the vBcl2 peptide disrupts the vBcl2-ORF55 interaction and effectively inhibits KSHV virion assembly. This study indicates that KSHV vBcl2 harbors at least three genetically separable functions to modulate both host cell death signaling and virion production and that the vBcl2 peptide can be developed as an anti-KSHV therapeutic application.
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http://dx.doi.org/10.1128/JVI.00914-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790944PMC
February 2018

TRIM23 mediates virus-induced autophagy via activation of TBK1.

Nat Microbiol 2017 Nov 4;2(11):1543-1557. Epub 2017 Sep 4.

Department of Microbiology, The University of Chicago, Chicago, IL, 60637, USA.

Autophagy and interferon (IFN)-mediated innate immunity are critical antiviral defence mechanisms, and recent evidence indicated that tripartite motif (TRIM) proteins are important regulators of both processes. Although the role of TRIM proteins in modulating antiviral cytokine responses has been well established, much less is known about their involvement in autophagy in response to different viral pathogens. Through a targeted RNAi screen examining the relevance of selected TRIM proteins in autophagy induced by herpes simplex virus 1 (HSV-1), encephalomyocarditis virus (EMCV) and influenza A virus (IAV), we identified several TRIM proteins that regulate autophagy in a virus-species-specific manner, as well as a few TRIM proteins that were essential for autophagy triggered by all three viruses and rapamycin, among them TRIM23. TRIM23 was critical for autophagy-mediated restriction of multiple viruses, and this activity was dependent on both its RING E3 ligase and ADP-ribosylation factor (ARF) GTPase activity. Mechanistic studies revealed that unconventional K27-linked auto-ubiquitination of the ARF domain is essential for the GTP hydrolysis activity of TRIM23 and activation of TANK-binding kinase 1 (TBK1) by facilitating its dimerization and ability to phosphorylate the selective autophagy receptor p62. Our work identifies the TRIM23-TBK1-p62 axis as a key component of selective autophagy and further reveals a role for K27-linked ubiquitination in GTPase-dependent TBK1 activation.
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http://dx.doi.org/10.1038/s41564-017-0017-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658249PMC
November 2017

PRAS40 Connects Microenvironmental Stress Signaling to Exosome-Mediated Secretion.

Mol Cell Biol 2017 Oct 12;37(19). Epub 2017 Sep 12.

Department of Dermatology and Norris Comprehensive Cancer Center, University of Southern California Keck Medical Center, Los Angeles, California, USA

Secreted exosomes carrying lipids, proteins, and nucleic acids conduct cell-cell communications within the microenvironment of both physiological and pathological conditions. Exosome secretion is triggered by extracellular or intracellular stress signals. Little is known, however, about the signal transduction between stress cues and exosome secretion. To identify the linker protein, we took advantage of a unique finding in human keratinocytes. In these cells, although transforming growth factor alpha (TGF-α) and epidermal growth factor (EGF) share the same EGF receptor and previously indistinguishable intracellular signaling networks, only TGF-α stimulation causes exosome-mediated secretion. However, deduction of EGF-activated pathways from TGFα-activated pathways in the same cells allowed us to identify the proline-rich Akt substrate of 40 kDa (PRAS40) as the unique downstream effector of TGF-α but not EGF signaling via threonine 308-phosphorylated Akt. PRAS40 knockdown (KD) or PRAS40 dominant-negative (DN) mutant overexpression blocks not only TGF-α- but also hypoxia- and HO-induced exosome secretion in a variety of normal and tumor cells. Site-directed mutagenesis and gene rescue studies show that Akt-mediated activation of PRAS40 via threonine 246 phosphorylation is both necessary and sufficient to cause exosome secretion without affecting the endoplasmic reticulum/Golgi pathway. Identification of PRAS40 as a linker protein paves the way for understanding how stress regulates exosome secretion under pathophysiological conditions.
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http://dx.doi.org/10.1128/MCB.00171-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599722PMC
October 2017

Autophagy regulates MAVS signaling activation in a phosphorylation-dependent manner in microglia.

Cell Death Differ 2017 02 4;24(2):276-287. Epub 2016 Nov 4.

The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.

Mitochondrial antiviral signaling (MAVS) protein has an important role in antiviral immunity and autoimmunity. However, the pathophysiological role of this signaling pathway, especially in the brain, remains elusive. Here we demonstrated that MAVS signaling existed and mediated poly(I:C)-induced inflammation in the brain. Along with the MAVS signaling activation, there was an induction of autophagic activation. Autophagy negatively regulated the activity of MAVS through direct binding of LC3 to the LIR motif Y(9)xxI(12) of MAVS. We also found that c-Abl kinase phosphorylated MAVS and regulated its interaction with LC3. Interestingly, tyrosine phosphorylation of MAVS was required for downstream signaling activation. Importantly, in vivo data showed that the deficiency of MAVS or c-Abl prevented MPTP-induced microglial activation and dopaminergic neuron loss. Together, our findings reveal the molecular mechanisms underlying the regulation of MAVS-dependent microglial activation in the nervous system, thus providing a potential target for the treatment of microglia-driven inflammatory brain diseases.
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http://dx.doi.org/10.1038/cdd.2016.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299710PMC
February 2017

Autophagy modulator plays a part in UV protection.

Autophagy 2016 09 20;12(9):1677-8. Epub 2016 Jul 20.

a Department of Molecular Microbiology and Immunology , University of Southern California , Los Angeles , CA , USA.

Ultraviolet (UV)-induced DNA damage is a major risk factor for skin cancers including melanoma. UVRAG, originally identified to complement UV sensitivity in xeroderma pigmentosum (XP), has since been implicated in modulating macroautophagy/autophagy, in coordinating different intracellular trafficking pathways, and in maintaining chromosomal stability. Intriguingly, our recent study has demonstrated that UVRAG plays an essential role in protecting cells from UV-induced DNA damage by activating the nucleotide excision repair (NER) pathway. Since NER is the major mechanism by which cells maintain DNA integrity against UV insult, the inactivation of UVRAG seen in some melanoma may impart these cells with an ability to accumulate high-load UV mutagenesis, leading to cancer progression. Thus, this property of UVRAG has untapped potential to be of fundamental importance in understanding the genetics and pathogenesis of human skin cancer.
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http://dx.doi.org/10.1080/15548627.2016.1196319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082777PMC
September 2016

Autophagic UVRAG Promotes UV-Induced Photolesion Repair by Activation of the CRL4(DDB2) E3 Ligase.

Mol Cell 2016 05;62(4):507-19

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address:

UV-induced DNA damage, a major risk factor for skin cancers, is primarily repaired by nucleotide excision repair (NER). UV radiation resistance-associated gene (UVRAG) is a tumor suppressor involved in autophagy. It was initially isolated as a cDNA partially complementing UV sensitivity in xeroderma pigmentosum (XP), but this was not explored further. Here we show that UVRAG plays an integral role in UV-induced DNA damage repair. It localizes to photolesions and associates with DDB1 to promote the assembly and activity of the DDB2-DDB1-Cul4A-Roc1 (CRL4(DDB2)) ubiquitin ligase complex, leading to efficient XPC recruitment and global genomic NER. UVRAG depletion decreased substrate handover to XPC and conferred UV-damage hypersensitivity. We confirmed the importance of UVRAG for UV-damage tolerance using a Drosophila model. Furthermore, increased UV-signature mutations in melanoma correlate with reduced expression of UVRAG. Our results identify UVRAG as a regulator of CRL4(DDB2)-mediated NER and suggest that its expression levels may influence melanoma predisposition.
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http://dx.doi.org/10.1016/j.molcel.2016.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875571PMC
May 2016

Autophagy interaction with herpes simplex virus type-1 infection.

Autophagy 2016 2;12(3):451-9. Epub 2016 Mar 2.

a Department of Molecular Microbiology and Immunology , Keck Medical School, University of Southern California , Los Angeles , CA , USA.

More than 50% of the U.S. population is infected with herpes simplex virus type-I (HSV-1) and global infectious estimates are nearly 90%. HSV-1 is normally seen as a harmless virus but debilitating diseases can arise, including encephalitis and ocular diseases. HSV-1 is unique in that it can undermine host defenses and establish lifelong infection in neurons. Viral reactivation from latency may allow HSV-1 to lay siege to the brain (Herpes encephalitis). Recent advances maintain that HSV-1 proteins act to suppress and/or control the lysosome-dependent degradation pathway of macroautophagy (hereafter autophagy) and consequently, in neurons, may be coupled with the advancement of HSV-1-associated pathogenesis. Furthermore, increasing evidence suggests that HSV-1 infection may constitute a gradual risk factor for neurodegenerative disorders. The relationship between HSV-1 infection and autophagy manipulation combined with neuropathogenesis may be intimately intertwined demanding further investigation.
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http://dx.doi.org/10.1080/15548627.2016.1139262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836034PMC
December 2016

RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer.

Nat Commun 2016 Feb 26;7:10751. Epub 2016 Feb 26.

Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.

Recent high-throughput studies revealed recurrent RUNX1 mutations in breast cancer, specifically in oestrogen receptor-positive (ER(+)) tumours. However, mechanisms underlying the implied RUNX1-mediated tumour suppression remain elusive. Here, by depleting mammary epithelial cells of RUNX1 in vivo and in vitro, we demonstrate combinatorial regulation of AXIN1 by RUNX1 and oestrogen. RUNX1 and ER occupy adjacent elements in AXIN1's second intron, and RUNX1 antagonizes oestrogen-mediated AXIN1 suppression. Accordingly, RNA-seq and immunohistochemical analyses demonstrate an ER-dependent correlation between RUNX1 and AXIN1 in tumour biopsies. RUNX1 loss in ER(+) mammary epithelial cells increases β-catenin, deregulates mitosis and stimulates cell proliferation and expression of stem cell markers. However, it does not stimulate LEF/TCF, c-Myc or CCND1, and it does not accelerate G1/S cell cycle phase transition. Finally, RUNX1 loss-mediated deregulation of β-catenin and mitosis is ameliorated by AXIN1 stabilization in vitro, highlighting AXIN1 as a potential target for the management of ER(+) breast cancer.
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http://dx.doi.org/10.1038/ncomms10751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773428PMC
February 2016

MicroRNAs: an emerging player in autophagy.

ScienceOpen Res 2015;2015. Epub 2014 Dec 22.

Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA.

Autophagy is an evolutionarily conserved self-digestion process for the quality control of intracellular entities in eukaryotes. In the past few years, mounting evidence indicates that microRNAs (miRNAs)-mediated post-transcriptional regulation of gene expression represents an integral part of the autophagy regulatory network and may have a substantial effect on autophagy-related physiological and pathological conditions including cancer. Herein, we examine some of the molecular mechanisms by which miRNAs manipulate the autophagic machinery to maintain cellular homeostasis and their biological outputs during cancer development. A better understanding of interaction between miRNAs and cellular autophagy may ultimately benefit future cancer diagnostic and anticancer therapeutics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700926PMC
http://dx.doi.org/10.14293/S2199-1006.1.SOR-LIFE.A181CU.v1DOI Listing
December 2014
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