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News & Views |
Saving ribosomal proteins for later
Disruption of ribosome assembly results in the accumulation of aggregation-prone ‘orphaned’ ribosomal proteins that are toxic to cells if left unchecked. A study finds that cells store such ribosomal proteins during heat shock to enable a quick recovery of ribosome assembly after the removal of this stress.
- Joshua J. Black
- & Rachel Green
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Article |
Adaptive preservation of orphan ribosomal proteins in chaperone-dispersed condensates
Ali et al. show that, during heat shock, aggregation-prone orphan ribosomal proteins form nucleolar-associated condensates that are kept in a liquid-like and reusable state through Hsp70 and its co-chaperones.
- Asif Ali
- , Rania Garde
- & David Pincus
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Article
| Open Access
ER-associated RNA silencing promotes ER quality control
Efstathiou et al. describe an Argonaute-dependent endoplasmic reticulum (ER)-associated RNA silencing pathway that acts together with ER-associated protein degradation to preserve ER homeostasis and function.
- Sotirios Efstathiou
- , Franziska Ottens
- & Thorsten Hoppe
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Letter |
The chaperone DNAJB6 surveils FG-nucleoporins and is required for interphase nuclear pore complex biogenesis
Kuiper et al. and Prophet et al. implicate DNAJB6/HSP70 chaperone activities in the biogenesis of the nuclear pore complex permeability barrier and find that disease-linked nuclear envelope blebs are enriched in nucleoporin and chaperone condensates.
- E. F. Elsiena Kuiper
- , Paola Gallardo
- & Steven Bergink
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News & Views |
Finding a chaperone for TDP-43
Aggregation of the RNA-binding protein TDP-43 is commonly observed in neurodegenerative disorders. A new study reveals that this process may be blocked by HSPB1, a small heat shock protein that can also regulate TDP-43 phase separation. This may be relevant to neurodegeneration, as loss of HSPB1 correlates with TDP-43 pathology.
- Yuna M. Ayala
- & Zachary R. Grese
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Article |
Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition
Lu et al. report that biomolecular condensation of cytoplasmic TDP-43 is regulated by HSPB1 to maintain its droplets in liquid and not gel/solid structures and that HSPB1 is decreased in spinal motor neurons with TDP-43 pathology in patients with amyotrophic lateral sclerosis.
- Shan Lu
- , Jiaojiao Hu
- & Don W. Cleveland
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News & Views |
Centrosomes grow aggresomes to clear waste
Overload of proteasomal clearance triggers formation of a large protein inclusion called the aggresome, which shares similarities with protein aggregates seen in neurodegenerative diseases such as Huntington’s. A new study uncovers how centrosome and centriolar satellite components facilitate stepwise assembly of aggresomes.
- Elisa Vitiello
- & Fanni Gergely
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Article
| Open Access
Aggresome assembly at the centrosome is driven by CP110–CEP97–CEP290 and centriolar satellites
Prosser et al. report that centriolar satellite and centrosomal proteins seed aggresomes, perinuclear inclusions of misfolded proteins, and may play a role in aggresome formation during senescence and huntingtin aggregation.
- Suzanna L. Prosser
- , Johnny Tkach
- & Laurence Pelletier
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Article |
Reversible phase separation of HSF1 is required for an acute transcriptional response during heat shock
Zhang, Shao and coworkers report that HSF1 forms small condensates at its target gene loci to promote their transcription during acute heat stress. The produced HSP70 proteins in turn disperse HSF1 condensates to shut off the heat-shock response.
- Hongchen Zhang
- , Shipeng Shao
- & Yujie Sun
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News & Views |
Metabolites control stress granule disassembly
Cells respond to stimuli by reorganizing their contents into subcellular structures. New research demonstrates that yeast pyruvate kinase Cdc19 interacts with fructose-1,6-bisphosphate to coordinate disassembly of stress granules. These findings reveal how proteins can directly sense the cellular energy state to facilitate adaptive reorganization.
- Christopher M. Jakobson
- & Daniel F. Jarosz
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Article |
Reversible amyloids of pyruvate kinase couple cell metabolism and stress granule disassembly
Cereghetti et al. report that the glycolytic metabolite fructose-1,6-bisphosphate initiates the disassembly of amyloids formed by the yeast pyruvate kinase Cdc19 to resume ATP production during stress recovery.
- Gea Cereghetti
- , Caroline Wilson-Zbinden
- & Matthias Peter
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Perspective |
Generic nature of the condensed states of proteins
In this Perspective, Fuxreiter and Vendruscolo discuss the fundamental nature of the droplet and amyloid states of proteins, the regulatory mechanisms controlling their formation, and the cellular functions associated with these condensed states.
- Monika Fuxreiter
- & Michele Vendruscolo
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Letter |
Protein quality control through endoplasmic reticulum-associated degradation maintains haematopoietic stem cell identity and niche interactions
Xu, Liu, Pen, Zhang et al. demonstrate that the SEL1L–HRD1 complex, which is part of the ERAD protein quality control machinery, safeguards haematopoietic stem cell identity and niche location by ensuring the haematopoietic stem cell surface expression of MPL.
- Longyong Xu
- , Xia Liu
- & Xi Chen
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News & Views |
Protein homeostasis from the outside in
Secretory proteins undergo multiple rounds of co- and post-translational quality control checks inside the cell, but how their integrity is maintained outside the cell is an emerging topic. A study establishes a model system to investigate how the extracellular proteome is protected and integrates its findings into existing immune pathways.
- Brant M. Webster
- , Holly K. Gildea
- & Andrew Dillin
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Letter |
HSF1 phase transition mediates stress adaptation and cell fate decisions
Gaglia et al. show, using single-cell imaging and analysis in human tumours, that phase transition of heat-shock factor 1 (HSF1) to form intranuclear stress bodies mediates cell-fate decisions underlying cell survival or death.
- Giorgio Gaglia
- , Rumana Rashid
- & Sandro Santagata
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Article |
Asymmetric inheritance of spindle microtubule-organizing centres preserves replicative lifespan
Yeast cells segregate the old spindle pole body into the bud. Manzano-López et al. report that inverted segregation accelerates ageing due to aberrant partition of protein aggregates and damaged mitochondria.
- Javier Manzano-López
- , Laura Matellán
- & Fernando Monje-Casas
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Article |
Mitochondrial protein-induced stress triggers a global adaptive transcriptional programme
Boos et al. show that impairing mitochondrial protein import induces a global transcriptional response to activate the ubiquitin–proteasome system and heat stress response and repress oxidative phosphorylation genes.
- Felix Boos
- , Lena Krämer
- & Johannes M. Herrmann
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Article |
Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification
Şentürk et al. show that ubiquilins bind v-ATPase to control lysosome acidity, mTOR signalling and autophagic flux in neurons, and that feeding flies with acidic nanoparticles ameliorates defective autophagy in ubiquilin mutants.
- Mümine Şentürk
- , Guang Lin
- & Hugo J. Bellen
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Letter |
Single particle trajectories reveal active endoplasmic reticulum luminal flow
Using super-resolution microscopy, tracking of single particle trajectories of endoplasmic reticulum (ER) luminal proteins traversing tubular ER, and measuring ER dynamics, Holcman et al. show that ER content is propelled by active luminal flow.
- David Holcman
- , Pierre Parutto
- & Edward Avezov
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Article |
IRE1α governs cytoskeleton remodelling and cell migration
through a direct interaction with filamin A
Urra et al. discover that IRE1α, an ER stress mediator, interacts with filamin A and controls actin dynamics and cell migration in mouse, Drosophila and zebrafish models in a manner independent of its canonical function.
- Hery Urra
- , Daniel R. Henriquez
- & Claudio Hetz
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News & Views |
Protein quality and miRNA slicing get into phase
Phase separation can build assemblies and regulate biological function. Two articles link specific forms of protein and RNA degradation to phase separation. The polyubiquitin shuttle factor UBQLN2 localizes to stress granules where it may extract ubiquitinated proteins, and the miRISC complex functions through phase separation.
- Tanja Mittag
- & Nicolas L. Fawzi
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News & Views |
Preserving protein function through reversible aggregation
It is generally accepted that protein function depends on a defined 3D structure, with unfolding and aggregation dealing a final blow to functionality. A study now shows that the regulated exposure of an unstructured region in yeast pyruvate kinase triggers reversible aggregation to preserve protein function under stress.
- Jörg Höhfeld
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Article |
Reversible protein aggregation is a protective mechanism to ensure cell cycle restart after stress
Saad et al. identify stress-induced reversible protein aggregation as a protective mechanism to ensure cell cycle resumption and cell survival after stress in yeast.
- Shady Saad
- , Gea Cereghetti
- & Reinhard Dechant
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News & Views |
CPEB4 links the clock and the UPR to protect the liver
Under misfolded protein stress, the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis, or commits the cell to apoptosis. A study now uncovers how the UPR is governed by the circadian clock to adjust ER protein-folding capacity to metabolic demand and protect against liver damage.
- Paul C. Moore
- & Scott A. Oakes
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Article |
Circadian- and UPR-dependent control of CPEB4 mediates a translational response to counteract hepatic steatosis under ER stress
Maillo et al. show that in hepatocytes ER stress upregulates CPEB4 through the UPR and circadian clock, leading to CPEB4-mediated translation for mitochondrial and ER homeostasis. CPEB4 loss leads to ageing- and high fat diet-induced liver steatosis.
- Carlos Maillo
- , Judit Martín
- & Raúl Méndez
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Article |
IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation
Through a proteomics approach, Qi and colleagues and Long and colleagues identify the sensor of the unfolded protein response IRE1α as an endogenous substrate of the E3 ubiquitin ligase involved in ER-associated degradation, Hrd1.
- Shengyi Sun
- , Guojun Shi
- & Ling Qi
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News & Views |
How cells coordinate waste removal through their major proteolytic pathways
The eukaryotic cell uses two complex machineries to degrade unwanted proteins. The first is the ubiquitin–proteasome system and the second is autophagy. A new study contributes to our understanding of how the two systems interconnect to coordinate protein degradation.
- Sascha Martens
- & Andreas Bachmair
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Review Article |
Proteostasis control by the unfolded protein response
- Claudio Hetz
- , Eric Chevet
- & Scott A. Oakes
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Article |
Amino-terminal arginylation targets endoplasmic reticulum chaperone BiP for autophagy through p62 binding
Kim and colleagues and Kwon and colleagues reveal that amino-terminal arginylation of BiP promotes its targeting to autophagy adaptor p62 and subsequent lysosomal degradation of BiP, p62 and associated cargo.
- Hyunjoo Cha-Molstad
- , Ki Sa Sung
- & Yong Tae Kwon
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News & Views |
Rsp5/Nedd4 clears cells of heat-damaged proteins
Protein quality control systems protect cells from proteotoxicity caused by the accumulation of aberrantly folded polypeptides. The Rsp5 ubiquitin ligase (mammalian homologue Nedd4) is now identified as a major constituent of a clearance pathway that degrades misfolded cytosolic proteins after exposure to heat.
- Thomas Sommer
- , Annika Weber
- & Ernst Jarosch
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Article |
Rsp5/Nedd4 is the main ubiquitin ligase that targets cytosolic misfolded proteins following heat stress
Mayor and colleagues identify yeast Rsp5 (mammalian homologue Nedd4) as the main ubiquitin ligase responsible for the increased ubiquitylation following heat stress when Rsp5 targets cytosolic misfolded proteins for proteasome degradation.
- Nancy N. Fang
- , Gerard T. Chan
- & Thibault Mayor
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Article |
Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane
How misfolded proteins are extracted from the endoplasmic reticulum (ER) for degradation remains unclear. Sommer and colleagues demonstrate that following assembly into the HRD ligase complex, Der1 forms oligomers in the ER membrane and enables extraction of proteins from the ER lumen.
- Martin Mehnert
- , Thomas Sommer
- & Ernst Jarosch
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Article |
ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death
In the presence of stress stimuli, the endoplasmic reticulum either adapts the protein synthesis or triggers an apoptotic response, but the mechanisms underlying this decision are unknown. Kaufman and colleagues show that the ER stress response factors ATF4 and CHOP increase protein synthesis, which in turn induces oxidative stress and increased ATP consumption, leading to cell death during chronic ER stress.
- Jaeseok Han
- , Sung Hoon Back
- & Randal J. Kaufman
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Letter |
PARP16 is a tail-anchored endoplasmic reticulum protein required for the PERK- and IRE1α-mediated unfolded protein response
Chang and colleagues reveal that the poly(ADP-ribose) polymerase PARP16 participates in the endoplasmic reticulum (ER) stress response. They report that PARP16 is a transmembrane ER protein that PARsylates and activates PERK and IRE1α in response to ER stress.
- Miri Jwa
- & Paul Chang
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Article |
Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) lead to accumulation of proteins aggregates in airways. Mutated CFTR promotes transglutaminases-mediated crosslinking of beclin 1, a positive regulator of autophagy, to induce accumulation of LC3-binding protein p62 and prevent autophagic degradation of aggregates.
- Alessandro Luciani
- , Valeria Rachela Villella
- & Luigi Maiuri
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Letter |
Regulation of Rho GTPase crosstalk, degradation and activity by RhoGDI1
Rho guanine nucleotide dissociation inhibitors (RhoGDIs) bind to inactive Rho GTPases in the cytosol, but their function remains unclear. Several Rho GTPases are now shown to compete for RhoGDI binding and this is crucial for regulating Rho GTPase turnover and activation.
- Etienne Boulter
- , Rafael Garcia-Mata
- & Keith Burridge
Cyclophilin A supports translation of intrinsically disordered proteins and affects haematopoietic stem cell ageing