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Age-progressive interplay of HSP-proteostasis, ECM-cell junctions and biomechanics ensures C. elegans astroglial architecture
Neural circuit architecture must be maintained during an animal’s lifetime. Here, the authors show that a protective mechanism combining proteostasis and biomechanics supports the integrity of glial cells to environmental stressors.
- Francesca Coraggio
- , Mahak Bhushan
- & Georgia Rapti
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| Open Access
Methionine aminopeptidase 2 and its autoproteolysis product have different binding sites on the ribosome
The role of methionine aminopeptidase 2 (MAP2) at the ribosome goes beyond N-terminal methionine excision. Klein et al. use cryo-EM to identify a second MAP2 binding site on the ribosome, and describe the dynamic interactions of MAP2 at the ribosome.
- Marius A. Klein
- , Klemens Wild
- & Irmgard Sinning
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| Open Access
Orphan quality control by an SCF ubiquitin ligase directed to pervasive C-degrons
The prevalence and conservation of C-degrons across eukaryotes is unclear. Here, the authors perform an unbiased survey of C-degrons in budding yeast and identify a C-degron pathway of broad specificity operated by the SCFDas1 ubiquitin ligase.
- Ka-Yiu Edwin Kong
- , Susmitha Shankar
- & Anton Khmelinskii
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| Open Access
The heat shock protein LarA activates the Lon protease in response to proteotoxic stress
The Lon protease is an important protein degradation machine and is conserved across the three domains of life. Here, the authors describe a small proteotoxic stress-induced protein that functions as an allosteric activator of Lon.
- Deike J. Omnus
- , Matthias J. Fink
- & Kristina Jonas
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| Open Access
HSP47 levels determine the degree of body adiposity
A complex interplay of various backgrounds and conditions determines the body fat levels of individuals. Here, the authors identify HSP47 as a pivotal determinant of body adiposity which is abundantly expressed in fat tissue and influenced by factors such as diet, exercise, hormones, and genetics.
- Jihoon Shin
- , Shinichiro Toyoda
- & Iichiro Shimomura
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| Open Access
Loss of N-terminal acetyltransferase A activity induces thermally unstable ribosomal proteins and increases their turnover in Saccharomyces cerevisiae
N-terminal acetylation is a common modification with unclear function. Here, using multidimensional proteomics, the authors found that NatA-deficient yeast show increased ribosomal protein degradation and decreased ribosome thermostability, suggesting that N-terminal acetylation enhances proteome stability.
- Ulises H. Guzman
- , Henriette Aksnes
- & Jesper V. Olsen
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Article
| Open Access
Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity
The accumulation of cytotoxic deoxysphingolipids causes retinopathies through unknown mechanisms. Here the authors use retinal organoids to show that photoreceptor toxicity is mediated by unfolded protein response signaling.
- Jessica D. Rosarda
- , Sarah Giles
- & Kevin T. Eade
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Article
| Open Access
Artificial Hsp104-mediated systems for re-localizing protein aggregates
Protein aggregates are a hallmark of neurodegenerative disease and aging. Here, Fischbach et al. report engineered, artificial systems to re-localise or export protein aggregates from cells, with preliminary data showing that mHtt inclusions in S. cerevisiae may be cytotoxic.
- Arthur Fischbach
- , Angela Johns
- & Thomas Nyström
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Article
| Open Access
Recognition of an Ala-rich C-degron by the E3 ligase Pirh2
Incompletely synthesized nascent polypeptides resulting from ribosome stalling during translation are under surveillance by ribosome-associated quality control. Here, the authors report the molecular mechanism by which the E3 ligase Pirh2 targets the polyalanine tail of aberrant nascent chains for degradation via the C-degron pathway.
- Xiaolu Wang
- , Yao Li
- & Cheng Dong
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Article
| Open Access
The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system
Tau aggregates are associated with several neurodegenerative disorders. In this work, I. Saha and colleagues show that valosin-containing protein (VCP) recruited to Tau fibrils disaggregates them. However, this process comes at a cost: it generates seeding-active Tau species as byproduct.
- Itika Saha
- , Patricia Yuste-Checa
- & Mark S. Hipp
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Article
| Open Access
Conserved degronome features governing quality control associated proteolysis
How misfolded proteins are selected by the ubiquitin-conjugating system for elimination is largely unknown. Here, the authors identify conserved features of proteome-derived degradation signals, including amino acid and structural preferences, that trigger quality-control-associated proteolysis.
- Bayan Mashahreh
- , Shir Armony
- & Tommer Ravid
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Article
| Open Access
Thermosensation in Caenorhabditis elegans is linked to ubiquitin-dependent protein turnover via insulin and calcineurin signalling
Sensation of environmental changes is vital for organismal homeostasis. Here, the authors report that protein degradation in the gut of Caenorhabditis elegans is regulated through insulin and calcineurin signalling upon neuronal sensation of temperature changes.
- Alexandra Segref
- , Kavya L. Vakkayil
- & Thorsten Hoppe
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Article
| Open Access
Insights into the client protein release mechanism of the ATP-independent chaperone Spy
How ATP-independent chaperones release their clients without energy input remains enigmatic. Here the authors discover that chaperone Spy uses its long, disordered N terminus to facilitate client release through competitive, dynamic intramolecular interactions with Spy’s client binding surface.
- Wei He
- , Xinming Li
- & Shu Quan
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| Open Access
The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system
Targeted protein degradation is a promising approach for basic research and therapeutic applications. Here, the authors develop a targeted protein degradation platform called AUTOTAC to degrade oncoproteins and neurodegeneration-associated proteins via the p62-dependent autophagy-lysosome system.
- Chang Hoon Ji
- , Hee Yeon Kim
- & Yong Tae Kwon
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| Open Access
Mapping protein carboxymethylation sites provides insights into their role in proteostasis and cell proliferation
Accumulation of advanced glycation end products such as carboxymethyllysine (CML) has been associated with aging but their molecular roles are largely unclear. Here, the authors use proteomics to identify CML sites and show that CML formation affects protein homeostasis and cell proliferation.
- Simone Di Sanzo
- , Katrin Spengler
- & Regine Heller
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Article
| Open Access
Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation
Misfolded proteins are ubquitinated and subsequently condensed by cargo receptors for selective autophagy. Here, the authors use in vitro reconstitution to elegantly dissect how the receptors p62/SQSTM1, NBR1 and TAX1BP1 contribute to p62-ubiquitin condensate formation and degradation by autophagy.
- Eleonora Turco
- , Adriana Savova
- & Sascha Martens
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Article
| Open Access
Structures of the human LONP1 protease reveal regulatory steps involved in protease activation
The human mitochondrial protease LONP1 is an AAA+ ATP-dependent quality control protease. Here, the authors present the cryo-EM structures of human LONP1 in three distinct states and provide insights into the mechanism and regulation of this important protease.
- Mia Shin
- , Edmond R. Watson
- & Gabriel C. Lander
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Article
| Open Access
Microthermal-induced subcellular-targeted protein damage in cells on plasmonic nanosilver-modified surfaces evokes a two-phase HSP-p97/VCP response
Existing methods for inflicting cellular heat shock are limited by the time delay in achieving the desired temperature and the spatial precision that can be achieved. Here the authors report a method to induce focused thermal protein damage using plasmonic silver nanoparticles.
- Martin Mistrik
- , Zdenek Skrott
- & Jiri Bartek
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Article
| Open Access
Functional cooperativity between the trigger factor chaperone and the ClpXP proteolytic complex
ClpXP is the main ATP-dependent proteolytic complex in bacteria, is essential for maintaining cellular protein homeostasis and is also critical for bacterial pathogenesis. Here, the authors establish a functional link between ClpXP and trigger actor, a chaperone involved in the early stages of protein folding.
- Kamran Rizzolo
- , Angela Yeou Hsiung Yu
- & Walid A. Houry
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| Open Access
The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation
Hop, also known as Stip1 or Sti1, facilitates substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Characterization of proteostasis-related pathways in STIP1 knock-out cell lines reveals that in eukaryotes Stip1 modulates the balance between protein folding and degradation.
- Kaushik Bhattacharya
- , Lorenz Weidenauer
- & Didier Picard
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| Open Access
Wipi3 is essential for alternative autophagy and its loss causes neurodegeneration
Unlike canonical macroautophagy, alternative autophagy does not require the factors Atg5 and Atg7. Here, the authors show that Wipi3 is essential for alternative autophagy, but not for canonical autophagy, and that Wipi3 functions to maintain neuronal cells via mechanisms different from those of canonical autophagy.
- Hirofumi Yamaguchi
- , Shinya Honda
- & Shigeomi Shimizu
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Article
| Open Access
A salvage pathway maintains highly functional respiratory complex I
Maintenance and quality control of the mitochondrial respiratory chain complexes responsible for bulk energy production are unclear. Here, the authors show that the mitochondrial protease ClpXP is required for the rapid turnover of the core N-module of respiratory complex I, which happens independently of other modules in the complex.
- Karolina Szczepanowska
- , Katharina Senft
- & Aleksandra Trifunovic
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Article
| Open Access
Co-translational assembly of mammalian nuclear multisubunit complexes
Genes encoding protein complex subunits are often dispersed in the genome of eukaryotes, raising the question how these protein complexes assemble. Here, the authors provide evidence that mammalian nuclear transcription complexes are formed co-translationally to ensure specific and functional interactions.
- Ivanka Kamenova
- , Pooja Mukherjee
- & László Tora
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| Open Access
SMYD2 glutathionylation contributes to degradation of sarcomeric proteins
Ischemic reperfusion or nutrient deprivation that produces reactive oxygen species can lead to a loss of muscle contractile function. Here the authors show that glutathionylation of the lysine methyltransferase SMYD2 contributes to degradation or disassembly of sarcomeres.
- Dhanushka N. P. Munkanatta Godage
- , Garrett C. VanHecke
- & Young-Hoon Ahn
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Article
| Open Access
The ubiquitin ligase UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington’s disease patients
Induced pluripotent stem cells (iPSCs) suppress the aggregation of Huntington’s disease (HD) polyQ-expanded huntingtin (HTT). Here the authors show that proteasome activity determines the levels of mutant HTT in HD-iPSCs and find that UBR5 is a modulator of super-vigilant proteostasis of iPSCs.
- Seda Koyuncu
- , Isabel Saez
- & David Vilchez
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Article
| Open Access
Vms1p is a release factor for the ribosome-associated quality control complex
The ribosome-associated quality control complex (RQC) functions to disassemble stalled ribosomes. Here the authors find that the tRNA hydrolase Vms1 is involved in the release of nascent peptide from stalled ribosomes.
- Olga Zurita Rendón
- , Eric K. Fredrickson
- & Jared Rutter
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Article
| Open Access
TRIM11 activates the proteasome and promotes overall protein degradation by regulating USP14
The proteasome-bound ubiquitinase USP14 plays an important role in determining proteasome activity and substrate specificity. Here the authors show that TRIM11, a member of the mammalian tripartite motif family, regulates USP14 and is an important activator of the proteasome.
- Liang Chen
- , Guixin Zhu
- & Xiaolu Yang
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Article
| Open Access
UFD-2 is an adaptor-assisted E3 ligase targeting unfolded proteins
The U-box ubiquitin ligase UFD-2 is one of the most abundant components of the ubiquitin proteasome system in muscle cells. Here the authors perform in vitro and in vivo experiments and show that UFD-2 has E3 ligase activity and that it ubiquitinates unfolded myosin using the C. elegans myosin chaperone UNC-45 as an adaptor protein.
- Doris Hellerschmied
- , Max Roessler
- & Tim Clausen
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| Open Access
Structural basis of adaptor-mediated protein degradation by the tail-specific PDZ-protease Prc
MepS is a peptidoglycan (PG) cross-link specific hydrolase needed for cell wall expansion and its cellular levels must be tightly regulated. Here the authors present the structure of the MepS degrading protease Prc bound to its adaptor NlpI and propose a model how the NlpI-Prc complex mediates MepS degradation.
- Ming-Yuan Su
- , Nilanjan Som
- & Chung-I Chang
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Article
| Open Access
Ubiquitination of stalled ribosome triggers ribosome-associated quality control
Several protein quality control mechanisms are in place to trigger the rapid degradation of aberrant polypeptides and mRNAs. Here the authors describe a mechanism of ribosome-mediated quality control that involves the ubiquitination of ribosomal proteins by the E3 ubiquitin ligase Hel2/RQT1.
- Yoshitaka Matsuo
- , Ken Ikeuchi
- & Toshifumi Inada
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| Open Access
Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection
CtIP has a key role in DNA double-strand break repair as its role in resecting DNA at the break commits a cell to homologous recombination. Here the authors show that KLHL15 interacts with CtIP and regulates repair by controlling protein turnover.
- Lorenza P. Ferretti
- , Sarah-Felicitas Himmels
- & Alessandro A. Sartori
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Article
| Open Access
Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control
Defects in the DNA replication checkpoint can lead to genomic instability and cancer. Here the authors show that Cmr1/WDR76 participates in the DNA replication stress response and—along with several other components—defines a new cellular compartment that forms during cellular stress.
- Irene Gallina
- , Camilla Colding
- & Michael Lisby
Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants