Publications by authors named "Simon Alberti"

87 Publications

Hydrogen adsorption trends on two metal-doped NiP surfaces for optimal catalyst design.

Phys Chem Chem Phys 2021 May 10. Epub 2021 May 10.

Department of Chemistry and Materials Science, Aalto University, P.O. Box 16100, FI-00076 Aalto, Finland.

In this study, we looked at the hydrogen evolution reaction on the doubly doped Ni3P2 terminated Ni2P surface. Two Ni atoms in the first three layers of the Ni2P surface model were exchanged with two transition metal atoms. We limited our investigation to combinations of Al, Co, and Fe based on their individual effectiveness as Ni2P dopants in our previous computational studies. The DFT calculated hydrogen adsorption free energy was employed as a predictor of the materials' catalytic HER activity. Our results indicate that the combination of Co and Fe dopants most improves the catalytic activity of the surface through the creation of multiple novel and active catalytic sites.
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http://dx.doi.org/10.1039/d1cp00684cDOI Listing
May 2021

Small heat-shock protein HSPB3 promotes myogenesis by regulating the lamin B receptor.

Cell Death Dis 2021 May 6;12(5):452. Epub 2021 May 6.

Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125, Modena, Italy.

One of the critical events that regulates muscle cell differentiation is the replacement of the lamin B receptor (LBR)-tether with the lamin A/C (LMNA)-tether to remodel transcription and induce differentiation-specific genes. Here, we report that localization and activity of the LBR-tether are crucially dependent on the muscle-specific chaperone HSPB3 and that depletion of HSPB3 prevents muscle cell differentiation. We further show that HSPB3 binds to LBR in the nucleoplasm and maintains it in a dynamic state, thus promoting the transcription of myogenic genes, including the genes to remodel the extracellular matrix. Remarkably, HSPB3 overexpression alone is sufficient to induce the differentiation of two human muscle cell lines, LHCNM2 cells, and rhabdomyosarcoma cells. We also show that mutant R116P-HSPB3 from a myopathy patient with chromatin alterations and muscle fiber disorganization, forms nuclear aggregates that immobilize LBR. We find that R116P-HSPB3 is unable to induce myoblast differentiation and instead activates the unfolded protein response. We propose that HSPB3 is a specialized chaperone engaged in muscle cell differentiation and that dysfunctional HSPB3 causes neuromuscular disease by deregulating LBR.
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http://dx.doi.org/10.1038/s41419-021-03737-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102500PMC
May 2021

Reciprocal regulation of cellular mechanics and metabolism.

Nat Metab 2021 04 19;3(4):456-468. Epub 2021 Apr 19.

Medical Systems Biophysics and Bioengineering, Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, Leiden, the Netherlands.

Metabolism and mechanics are intrinsically intertwined. External forces, sensed through the cytoskeleton or distortion of the cell and organelles, induce metabolic changes in the cell. The resulting changes in metabolism, in turn, feed back to regulate every level of cell biology, including the mechanical properties of cells and tissues. Here we examine the links between metabolism and mechanics, highlighting signalling pathways involved in the regulation and response to cellular mechanosensing. We consider how forces and metabolism regulate one another through nanoscale molecular sensors, micrometre-scale cytoskeletal networks, organelles and dynamic biomolecular condensates. Understanding this cross-talk will create diagnostic and therapeutic opportunities for metabolic disorders such as cancer, cardiovascular pathologies and obesity.
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http://dx.doi.org/10.1038/s42255-021-00384-wDOI Listing
April 2021

Hsp90-mediated regulation of DYRK3 couples stress granule disassembly and growth via mTORC1 signaling.

EMBO Rep 2021 May 19;22(5):e51740. Epub 2021 Mar 19.

Department of Biomedical, Metabolic and Neural Sciences, Centre for Neuroscience and Nanotechnology, University of Modena and Reggio Emilia, Modena, Italy.

Stress granules (SGs) are dynamic condensates associated with protein misfolding diseases. They sequester stalled mRNAs and signaling factors, such as the mTORC1 subunit raptor, suggesting that SGs coordinate cell growth during and after stress. However, the molecular mechanisms linking SG dynamics and signaling remain undefined. We report that the chaperone Hsp90 is required for SG dissolution. Hsp90 binds and stabilizes the dual-specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3) in the cytosol. Upon Hsp90 inhibition, DYRK3 dissociates from Hsp90 and becomes inactive. Inactive DYRK3 is subjected to two different fates: it either partitions into SGs, where it is protected from irreversible aggregation, or it is degraded. In the presence of Hsp90, DYRK3 is active and promotes SG disassembly, restoring mTORC1 signaling and translation. Thus, Hsp90 links stress adaptation and cell growth by regulating the activity of a key kinase involved in condensate disassembly and translation restoration.
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http://dx.doi.org/10.15252/embr.202051740DOI Listing
May 2021

Knotting behaviour of polymer chains in the melt state for soft-core models with and without slip-springs.

J Phys Condens Matter 2021 May 13;33(24). Epub 2021 May 13.

Technical University of Darmstadt, Eduard-Zintl-Institute for Inorganic and Physical Chemistry and Profile Area Thermofluids and Interfaces, Alarich-Weiss-Strasse 8, D-64287 Darmstadt, Germany.

We analyse the knotting behaviour of linear polymer melts in two types of soft-core models, namely dissipative-particle dynamics and hybrid-particle-field models, as well as their variants with slip-springs which are added to recover entangled polymer dynamics. The probability to form knots is found drastically higher in the hybrid-particle-field model compared to its parent hard-core molecular dynamics model. By comparing the knottedness in dissipative-particle dynamics and hybrid-particle-field models with and without slip-springs, we find the impact of slip-springs on the knotting properties to be negligible. As a dynamic property, we measure the characteristic time of knot formation and destruction, and find it to be (i) of the same order as single-monomer motion and (ii) independent of the chain length in all soft-core models. Knots are therefore formed and destroyed predominantly by the unphysical chain crossing. This work demonstrates that the addition of slip-springs does not alter the knotting behaviour, and it provides a general understanding of knotted structures in these two soft-core models of polymer melts.
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http://dx.doi.org/10.1088/1361-648X/abef25DOI Listing
May 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

Protein products of nonstop mRNA disrupt nucleolar homeostasis.

Cell Stress Chaperones 2021 May 22;26(3):549-561. Epub 2021 Feb 22.

Department of Biochemistry, Stanford University, Stanford, CA, 94305, USA.

Stalled mRNA translation results in the production of incompletely synthesized proteins that are targeted for degradation by ribosome-associated quality control (RQC). Here we investigated the fate of defective proteins translated from stall-inducing, nonstop mRNA that escape ubiquitylation by the RQC protein LTN1. We found that nonstop protein products accumulated in nucleoli and this localization was driven by polylysine tracts produced by translation of the poly(A) tails of nonstop mRNA. Nucleolar sequestration increased the solubility of invading proteins but disrupted nucleoli, altering their dynamics, morphology, and resistance to stress in cell culture and intact flies. Our work elucidates how stalled translation may affect distal cellular processes and may inform studies on the pathology of diseases caused by failures in RQC and characterized by nucleolar stress.
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http://dx.doi.org/10.1007/s12192-021-01200-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065075PMC
May 2021

Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions.

Nat Commun 2021 02 17;12(1):1085. Epub 2021 Feb 17.

Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.

Liquid-liquid phase separation of proteins underpins the formation of membraneless compartments in living cells. Elucidating the molecular driving forces underlying protein phase transitions is therefore a key objective for understanding biological function and malfunction. Here we show that cellular proteins, which form condensates at low salt concentrations, including FUS, TDP-43, Brd4, Sox2, and Annexin A11, can reenter a phase-separated regime at high salt concentrations. By bringing together experiments and simulations, we demonstrate that this reentrant phase transition in the high-salt regime is driven by hydrophobic and non-ionic interactions, and is mechanistically distinct from the low-salt regime, where condensates are additionally stabilized by electrostatic forces. Our work thus sheds light on the cooperation of hydrophobic and non-ionic interactions as general driving forces in the condensation process, with important implications for aberrant function, druggability, and material properties of biomolecular condensates.
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http://dx.doi.org/10.1038/s41467-021-21181-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889641PMC
February 2021

Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing.

Nat Rev Mol Cell Biol 2021 03 28;22(3):196-213. Epub 2021 Jan 28.

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.

Biomolecular condensates are membraneless intracellular assemblies that often form via liquid-liquid phase separation and have the ability to concentrate biopolymers. Research over the past 10 years has revealed that condensates play fundamental roles in cellular organization and physiology, and our understanding of the molecular principles, components and forces underlying their formation has substantially increased. Condensate assembly is tightly regulated in the intracellular environment, and failure to control condensate properties, formation and dissolution can lead to protein misfolding and aggregation, which are often the cause of ageing-associated diseases. In this Review, we describe the mechanisms and regulation of condensate assembly and dissolution, highlight recent advances in understanding the role of biomolecular condensates in ageing and disease, and discuss how cellular stress, ageing-related loss of homeostasis and a decline in protein quality control may contribute to the formation of aberrant, disease-causing condensates. Our improved understanding of condensate pathology provides a promising path for the treatment of protein aggregation diseases.
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http://dx.doi.org/10.1038/s41580-020-00326-6DOI Listing
March 2021

Protein phase separation and its role in tumorigenesis.

Elife 2020 11 3;9. Epub 2020 Nov 3.

Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.

Cancer is a disease characterized by uncontrolled cell proliferation, but the precise pathological mechanisms underlying tumorigenesis often remain to be elucidated. In recent years, condensates formed by phase separation have emerged as a new principle governing the organization and functional regulation of cells. Increasing evidence links cancer-related mutations to aberrantly altered condensate assembly, suggesting that condensates play a key role in tumorigenesis. In this review, we summarize and discuss the latest progress on the formation, regulation, and function of condensates. Special emphasis is given to emerging evidence regarding the link between condensates and the initiation and progression of cancers.
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http://dx.doi.org/10.7554/eLife.60264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609067PMC
November 2020

The plant response to heat requires phase separation.

Authors:
Simon Alberti

Nature 2020 09;585(7824):191-192

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http://dx.doi.org/10.1038/d41586-020-02442-xDOI Listing
September 2020

BAG3 and BAG6 differentially affect the dynamics of stress granules by targeting distinct subsets of defective polypeptides released from ribosomes.

Cell Stress Chaperones 2020 11 21;25(6):1045-1058. Epub 2020 Jul 21.

Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Stress granules (SGs) are dynamic ribonucleoprotein granules induced by environmental stresses. They play an important role in the stress response by integrating mRNA stability, translation, and signaling pathways. Recent work has connected SG dysfunction to neurodegenerative diseases. In these diseases, SG dynamics are impaired because of mutations in SG proteins or protein quality control factors. Impaired SG dynamics and delayed SG dissolution have also been observed for SGs that accumulate misfolding-prone defective ribosomal products (DRiPs). DRiP accumulation inside SGs is controlled by a surveillance system referred to as granulostasis and encompasses the molecular chaperones VCP and the HSPB8-BAG3-HSP70 complex. BAG3 is a member of the BAG family of proteins, which includes five additional members. One of these proteins, BAG6, is functionally related to BAG3 and able to assist degradation of DRiPs. However, whether BAG6 is involved in granulostasis is unknown. We report that BAG6 is not recruited into SGs induced by different types of stress, nor does it affect SG dynamics. BAG6 also does not replace BAG3's function in SG granulostasis. We show that BAG3 and BAG6 target different subsets of DRiPs, and BAG3 binding to DRiPs is mediated by HSPB8 and HSP70. Our data support the idea that SGs are sensitive to BAG3-HSP70-bound DRiPs but not to BAG6-bound DRiPs. Additionally, only BAG3 is strongly upregulated in the stress recovery phase, when SGs dissolve. These data exclude a role for BAG6 in granulostasis and point to a more specialized function in the clearance of a specific subset of DRiPs.
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http://dx.doi.org/10.1007/s12192-020-01141-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591658PMC
November 2020

Biomolecular condensates undergo a generic shear-mediated liquid-to-solid transition.

Nat Nanotechnol 2020 10 13;15(10):841-847. Epub 2020 Jul 13.

Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.

Membrane-less organelles resulting from liquid-liquid phase separation of biopolymers into intracellular condensates control essential biological functions, including messenger RNA processing, cell signalling and embryogenesis. It has recently been discovered that several such protein condensates can undergo a further irreversible phase transition, forming solid nanoscale aggregates associated with neurodegenerative disease. While the irreversible gelation of protein condensates is generally related to malfunction and disease, one case where the liquid-to-solid transition of protein condensates is functional, however, is that of silk spinning. The formation of silk fibrils is largely driven by shear, yet it is not known what factors control the pathological gelation of functional condensates. Here we demonstrate that four proteins and one peptide system, with no function associated with fibre formation, have a strong propensity to undergo a liquid-to-solid transition when exposed to even low levels of mechanical shear once present in their liquid-liquid phase separated form. Using microfluidics to control the application of shear, we generated fibres from single-protein condensates and characterized their structural and material properties as a function of shear stress. Our results reveal generic backbone-backbone hydrogen bonding constraints as a determining factor in governing this transition. These observations suggest that shear can play an important role in the irreversible liquid-to-solid transition of protein condensates, shed light on the role of physical factors in driving this transition in protein aggregation-related diseases and open a new route towards artificial shear responsive biomaterials.
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http://dx.doi.org/10.1038/s41565-020-0731-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116851PMC
October 2020

Filament formation by the translation factor eIF2B regulates protein synthesis in starved cells.

Biol Open 2020 07 8;9(7). Epub 2020 Jul 8.

Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany

Cells exposed to starvation have to adjust their metabolism to conserve energy and protect themselves. Protein synthesis is one of the major energy-consuming processes and as such has to be tightly controlled. Many mechanistic details about how starved cells regulate the process of protein synthesis are still unknown. Here, we report that the essential translation initiation factor eIF2B forms filaments in starved budding yeast cells. We demonstrate that filamentation is triggered by starvation-induced acidification of the cytosol, which is caused by an influx of protons from the extracellular environment. We show that filament assembly by eIF2B is necessary for rapid and efficient downregulation of translation. Importantly, this mechanism does not require the kinase Gcn2. Furthermore, analysis of site-specific variants suggests that eIF2B assembly results in enzymatically inactive filaments that promote stress survival and fast recovery of cells from starvation. We propose that translation regulation through filament assembly is an efficient mechanism that allows yeast cells to adapt to fluctuating environments.
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http://dx.doi.org/10.1242/bio.046391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358136PMC
July 2020

The Nuclear SUMO-Targeted Ubiquitin Quality Control Network Regulates the Dynamics of Cytoplasmic Stress Granules.

Mol Cell 2020 07 9;79(1):54-67.e7. Epub 2020 Jun 9.

Institute of Biochemistry II, Goethe University, Faculty of Medicine, Frankfurt, Germany. Electronic address:

Exposure of cells to heat or oxidative stress causes misfolding of proteins. To avoid toxic protein aggregation, cells have evolved nuclear and cytosolic protein quality control (PQC) systems. In response to proteotoxic stress, cells also limit protein synthesis by triggering transient storage of mRNAs and RNA-binding proteins (RBPs) in cytosolic stress granules (SGs). We demonstrate that the SUMO-targeted ubiquitin ligase (StUbL) pathway, which is part of the nuclear proteostasis network, regulates SG dynamics. We provide evidence that inactivation of SUMO deconjugases under proteotoxic stress initiates SUMO-primed, RNF4-dependent ubiquitylation of RBPs that typically condense into SGs. Impairment of SUMO-primed ubiquitylation drastically delays SG resolution upon stress release. Importantly, the StUbL system regulates compartmentalization of an amyotrophic lateral sclerosis (ALS)-associated FUS mutant in SGs. We propose that the StUbL system functions as surveillance pathway for aggregation-prone RBPs in the nucleus, thereby linking the nuclear and cytosolic axis of proteotoxic stress response.
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http://dx.doi.org/10.1016/j.molcel.2020.05.017DOI Listing
July 2020

Condensation of Ded1p Promotes a Translational Switch from Housekeeping to Stress Protein Production.

Cell 2020 05 30;181(4):818-831.e19. Epub 2020 Apr 30.

Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany; BIOTEC and CMCB, Technische Universität Dresden, Tatzberg 47/48, 01307 Dresden, Germany. Electronic address:

Cells sense elevated temperatures and mount an adaptive heat shock response that involves changes in gene expression, but the underlying mechanisms, particularly on the level of translation, remain unknown. Here we report that, in budding yeast, the essential translation initiation factor Ded1p undergoes heat-induced phase separation into gel-like condensates. Using ribosome profiling and an in vitro translation assay, we reveal that condensate formation inactivates Ded1p and represses translation of housekeeping mRNAs while promoting translation of stress mRNAs. Testing a variant of Ded1p with altered phase behavior as well as Ded1p homologs from diverse species, we demonstrate that Ded1p condensation is adaptive and fine-tuned to the maximum growth temperature of the respective organism. We conclude that Ded1p condensation is an integral part of an extended heat shock response that selectively represses translation of housekeeping mRNAs to promote survival under conditions of severe heat stress.
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http://dx.doi.org/10.1016/j.cell.2020.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237889PMC
May 2020

RNA-Induced Conformational Switching and Clustering of G3BP Drive Stress Granule Assembly by Condensation.

Cell 2020 04;181(2):346-361.e17

Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universität Dresden, Tatzberg 47/49, 01307 Dresden, Germany.

Stressed cells shut down translation, release mRNA molecules from polysomes, and form stress granules (SGs) via a network of interactions that involve G3BP. Here we focus on the mechanistic underpinnings of SG assembly. We show that, under non-stress conditions, G3BP adopts a compact auto-inhibited state stabilized by electrostatic intramolecular interactions between the intrinsically disordered acidic tracts and the positively charged arginine-rich region. Upon release from polysomes, unfolded mRNAs outcompete G3BP auto-inhibitory interactions, engendering a conformational transition that facilitates clustering of G3BP through protein-RNA interactions. Subsequent physical crosslinking of G3BP clusters drives RNA molecules into networked RNA/protein condensates. We show that G3BP condensates impede RNA entanglement and recruit additional client proteins that promote SG maturation or induce a liquid-to-solid transition that may underlie disease. We propose that condensation coupled to conformational rearrangements and heterotypic multivalent interactions may be a general principle underlying RNP granule assembly.
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http://dx.doi.org/10.1016/j.cell.2020.03.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181197PMC
April 2020

Reorganization of budding yeast cytoplasm upon energy depletion.

Mol Biol Cell 2020 06 15;31(12):1232-1245. Epub 2020 Apr 15.

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany.

Yeast cells, when exposed to stress, can enter a protective state in which cell division, growth, and metabolism are down-regulated. They remain viable in this state until nutrients become available again. How cells enter this protective survival state and what happens at a cellular and subcellular level are largely unknown. In this study, we used electron tomography to investigate stress-induced ultrastructural changes in the cytoplasm of yeast cells. After ATP depletion, we observed significant cytosolic compaction and extensive cytoplasmic reorganization, as well as the emergence of distinct membrane-bound and membraneless organelles. Using correlative light and electron microscopy, we further demonstrated that one of these membraneless organelles was generated by the reversible polymerization of eukaryotic translation initiation factor 2B, an essential enzyme in the initiation of protein synthesis, into large bundles of filaments. The changes we observe are part of a stress-induced survival strategy, allowing yeast cells to save energy, protect proteins from degradation, and inhibit protein functionality by forming assemblies of proteins.
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http://dx.doi.org/10.1091/mbc.E20-02-0125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353153PMC
June 2020

Nucleolus: A Liquid Droplet Compartment for Misbehaving Proteins.

Curr Biol 2019 10;29(19):R930-R932

Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. Electronic address:

A new study reports an unexpected function of the nucleolus as a protein quality control compartment for misfolded and aggregation-prone proteins. These findings have important implications for protein misfolding diseases.
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http://dx.doi.org/10.1016/j.cub.2019.08.013DOI Listing
October 2019

Liquid-Liquid Phase Separation in Disease.

Annu Rev Genet 2019 12 20;53:171-194. Epub 2019 Aug 20.

BioMedical Center (BMC), Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany; email:

We have made rapid progress in recent years in identifying the genetic causes of many human diseases. However, despite this recent progress, our mechanistic understanding of these diseases is often incomplete. This is a problem because it limits our ability to develop effective disease treatments. To overcome this limitation, we need new concepts to describe and comprehend the complex mechanisms underlying human diseases. Condensate formation by phase separation emerges as a new principle to explain the organization of living cells. In this review, we present emerging evidence that aberrant forms of condensates are associated with many human diseases, including cancer, neurodegeneration, and infectious diseases. We examine disease mechanisms driven by aberrant condensates, and we point out opportunities for therapeutic interventions. We conclude that phase separation provides a useful new framework to understand and fight some of the most severe human diseases.
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http://dx.doi.org/10.1146/annurev-genet-112618-043527DOI Listing
December 2019

Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin.

EMBO J 2019 08 4;38(15):e101341. Epub 2019 Jul 4.

Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Nuclear protein aggregation has been linked to genome instability and disease. The main source of aggregation-prone proteins in cells is defective ribosomal products (DRiPs), which are generated by translating ribosomes in the cytoplasm. Here, we report that DRiPs rapidly diffuse into the nucleus and accumulate in nucleoli and PML bodies, two membraneless organelles formed by liquid-liquid phase separation. We show that nucleoli and PML bodies act as dynamic overflow compartments that recruit protein quality control factors and store DRiPs for later clearance. Whereas nucleoli serve as constitutive overflow compartments, PML bodies are stress-inducible overflow compartments for DRiPs. If DRiPs are not properly cleared by chaperones and proteasomes due to proteostasis impairment, nucleoli undergo amyloidogenesis and PML bodies solidify. Solid PML bodies immobilize 20S proteasomes and limit the recycling of free ubiquitin. Ubiquitin depletion, in turn, compromises the formation of DNA repair compartments at fragile chromosomal sites, ultimately threatening cell survival.
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http://dx.doi.org/10.15252/embj.2018101341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669919PMC
August 2019

Proteome-wide signatures of function in highly diverged intrinsically disordered regions.

Elife 2019 07 2;8. Epub 2019 Jul 2.

Department of Cell and Systems Biology, University of Toronto, Toronto, Canada.

Intrinsically disordered regions make up a large part of the proteome, but the sequence-to-function relationship in these regions is poorly understood, in part because the primary amino acid sequences of these regions are poorly conserved in alignments. Here we use an evolutionary approach to detect molecular features that are preserved in the amino acid sequences of orthologous intrinsically disordered regions. We find that most disordered regions contain multiple molecular features that are preserved, and we define these as 'evolutionary signatures' of disordered regions. We demonstrate that intrinsically disordered regions with similar evolutionary signatures can rescue function in vivo, and that groups of intrinsically disordered regions with similar evolutionary signatures are strongly enriched for functional annotations and phenotypes. We propose that evolutionary signatures can be used to predict function for many disordered regions from their amino acid sequences.
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http://dx.doi.org/10.7554/eLife.46883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634968PMC
July 2019

ALS and FTD: Where RNA metabolism meets protein quality control.

Semin Cell Dev Biol 2020 03 1;99:183-192. Epub 2019 Jul 1.

Centre for Neuroscience and Nanotechnology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. Electronic address:

Recent genetic and biochemical evidence has improved our understanding of the pathomechanisms that lead to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases with overlapping symptoms and causes. Impaired RNA metabolism, enhanced aggregation of protein-RNA complexes, aberrant formation of ribonucleoprotein (RNP) granules and dysfunctional protein clearance via autophagy are emerging as crucial events in ALS/FTD pathogenesis. Importantly, these processes interact at the molecular level, converging on a common pathogenic cascade. In this review, we summarize key principles underlying ALS and FTD, and we discuss how mutations in genes involved in RNA metabolism, protein quality control and protein degradation meet mechanistically to impair the functionality and dynamics of RNP granules, and how this leads to cellular toxicity and death. Finally, we describe recent advances in understanding signaling pathways that become dysfunctional in ALS/FTD, partly due to altered RNP granule dynamics, but also with stress granule-independent mechanisms and, thus could be promising targets for future therapeutic intervention.
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http://dx.doi.org/10.1016/j.semcdb.2019.06.003DOI Listing
March 2020

The prion-like domain of Drosophila Imp promotes axonal transport of RNP granules in vivo.

Nat Commun 2019 06 13;10(1):2593. Epub 2019 Jun 13.

University Côte d'Azur, CNRS, Inserm, iBV, Nice, 06100, France.

Prion-like domains (PLDs), defined by their low sequence complexity and intrinsic disorder, are present in hundreds of human proteins. Although gain-of-function mutations in the PLDs of neuronal RNA-binding proteins have been linked to neurodegenerative disease progression, the physiological role of PLDs and their range of molecular functions are still largely unknown. Here, we show that the PLD of Drosophila Imp, a conserved component of neuronal ribonucleoprotein (RNP) granules, is essential for the developmentally-controlled localization of Imp RNP granules to axons and regulates in vivo axonal remodeling. Furthermore, we demonstrate that Imp PLD restricts, rather than promotes, granule assembly, revealing a novel modulatory function for PLDs in RNP granule homeostasis. Swapping the position of Imp PLD compromises RNP granule dynamic assembly but not transport, suggesting that these two functions are uncoupled. Together, our study uncovers a physiological function for PLDs in the spatio-temporal control of neuronal RNP assemblies.
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http://dx.doi.org/10.1038/s41467-019-10554-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565635PMC
June 2019

FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy.

Acta Neuropathol 2019 07 1;138(1):67-84. Epub 2019 Apr 1.

Technische Universität Dresden, Center for Regenerative Therapies Dresden, Fetscherstr. 105, 01307, Dresden, Germany.

Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration and associated with aggregation of nuclear RNA-binding proteins (RBPs), including FUS. How FUS aggregation and neurodegeneration are prevented in healthy motor neurons remain critically unanswered questions. Here, we use a combination of ALS patient autopsy tissue and induced pluripotent stem cell-derived neurons to study the effects of FUS mutations on RBP homeostasis. We show that FUS' tendency to aggregate is normally buffered by interacting RBPs, but this buffering is lost when FUS mislocalizes to the cytoplasm due to ALS mutations. The presence of aggregation-prone FUS in the cytoplasm causes imbalances in RBP homeostasis that exacerbate neurodegeneration. However, enhancing autophagy using small molecules reduces cytoplasmic FUS, restores RBP homeostasis and rescues motor function in vivo. We conclude that disruption of RBP homeostasis plays a critical role in FUS-ALS and can be treated by stimulating autophagy.
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http://dx.doi.org/10.1007/s00401-019-01998-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570784PMC
July 2019

ERα condensates: chronic stimulation is hard to ignore.

Nat Struct Mol Biol 2019 03;26(3):153-154

Max-Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany.

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http://dx.doi.org/10.1038/s41594-019-0198-xDOI Listing
March 2019

Small heat shock proteins: multifaceted proteins with important implications for life.

Cell Stress Chaperones 2019 03 13;24(2):295-308. Epub 2019 Feb 13.

Laboratory of Cell and Developmental Genetics, IBIS, and Department of Molecular Biology, Medical Biochemistry and Pathology, Medical School, Université Laval, QC, Québec, G1V 0A6, Canada.

Small Heat Shock Proteins (sHSPs) evolved early in the history of life; they are present in archaea, bacteria, and eukaryota. sHSPs belong to the superfamily of molecular chaperones: they are components of the cellular protein quality control machinery and are thought to act as the first line of defense against conditions that endanger the cellular proteome. In plants, sHSPs protect cells against abiotic stresses, providing innovative targets for sustainable agricultural production. In humans, sHSPs (also known as HSPBs) are associated with the development of several neurological diseases. Thus, manipulation of sHSP expression may represent an attractive therapeutic strategy for disease treatment. Experimental evidence demonstrates that enhancing the chaperone function of sHSPs protects against age-related protein conformation diseases, which are characterized by protein aggregation. Moreover, sHSPs can promote longevity and healthy aging in vivo. In addition, sHSPs have been implicated in the prognosis of several types of cancer. Here, sHSP upregulation, by enhancing cellular health, could promote cancer development; on the other hand, their downregulation, by sensitizing cells to external stressors and chemotherapeutics, may have beneficial outcomes. The complexity and diversity of sHSP function and properties and the need to identify their specific clients, as well as their implication in human disease, have been discussed by many of the world's experts in the sHSP field during a dedicated workshop in Québec City, Canada, on 26-29 August 2018.
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http://dx.doi.org/10.1007/s12192-019-00979-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439001PMC
March 2019

Considerations and Challenges in Studying Liquid-Liquid Phase Separation and Biomolecular Condensates.

Cell 2019 01;176(3):419-434

Department for Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

Evidence is now mounting that liquid-liquid phase separation (LLPS) underlies the formation of membraneless compartments in cells. This realization has motivated major efforts to delineate the function of such biomolecular condensates in normal cells and their roles in contexts ranging from development to age-related disease. There is great interest in understanding the underlying biophysical principles and the specific properties of biological condensates with the goal of bringing insights into a wide range of biological processes and systems. The explosion of physiological and pathological contexts involving LLPS requires clear standards for their study. Here, we propose guidelines for rigorous experimental characterization of LLPS processes in vitro and in cells, discuss the caveats of common experimental approaches, and point out experimental and theoretical gaps in the field.
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http://dx.doi.org/10.1016/j.cell.2018.12.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445271PMC
January 2019

Protein Phase Separation as a Stress Survival Strategy.

Cold Spring Harb Perspect Biol 2019 06 3;11(6). Epub 2019 Jun 3.

Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.

Cells under stress must adjust their physiology, metabolism, and architecture to adapt to the new conditions. Most importantly, they must down-regulate general gene expression, but at the same time induce synthesis of stress-protective factors, such as molecular chaperones. Here, we investigate how the process of phase separation is used by cells to ensure adaptation to stress. We summarize recent findings and propose that the solubility of important translation factors is specifically affected by changes in physical-chemical parameters such temperature or pH and modulated by intrinsically disordered prion-like domains. These stress-triggered changes in protein solubility induce phase separation into condensates that regulate the activity of the translation factors and promote cellular fitness. Prion-like domains play important roles in this process as environmentally regulated stress sensors and modifier sequences that determine protein solubility and phase behavior. We propose that protein phase separation is an evolutionary conserved feature of proteins that cells harness to regulate adaptive stress responses and ensure survival in extreme environmental conditions.
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http://dx.doi.org/10.1101/cshperspect.a034058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546044PMC
June 2019

Phase changes in neurotransmission.

Science 2018 08;361(6402):548-549

Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.

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http://dx.doi.org/10.1126/science.aau5477DOI Listing
August 2018