scholarly journals Mitochondrial antiviral-signalling protein is a client of the BAG6 protein quality control complex

2021 ◽  
Author(s):  
Peristera Roboti ◽  
Craig Lawless ◽  
Stephen High
Keyword(s):  
Quality Control ◽  
Cellular Response ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Innate Immune ◽  
Control Factor ◽  
Stable Complex ◽  
Summary Statement ◽  
Ta Proteins ◽  
Control Complex

ABSTRACTThe heterotrimeric BAG6 complex coordinates the direct handover of newly synthesised tail-anchored (TA) membrane proteins from an SGTA-bound preloading complex to the endoplasmic reticulum (ER) delivery component TRC40. In contrast, defective precursors, including aberrant TA proteins, form a stable complex with this cytosolic protein quality control factor, enabling such clients to be either productively re-routed or selectively degraded. We identify the mitochondrial TA protein MAVS (mitochondrial antiviral-signalling protein) as an endogenous client of both SGTA and the BAG6 complex. Our data suggest that the BAG6 complex binds to a cytosolic pool of MAVS before its misinsertion into the ER membrane, from where it can subsequently be removed via ATP13A1-mediated dislocation. This BAG6- associated fraction of MAVS is dynamic and responds to the activation of an innate immune response, suggesting that BAG6 may modulate the pool of MAVS that is available for coordinating the cellular response to viral infection.SUMMARY STATEMENTMitochondrial antiviral-signalling (MAVS) protein is a favoured client of the cytosolic BAG6 complex. We discuss how this dynamic interaction may modulate MAVS biogenesis at signalling membranes.

scholarly journals Molecular chaperones and stress-inducible protein-sorting factors coordinate the spatiotemporal distribution of protein aggregates

2012 ◽  
Vol 23 (16) ◽  
pp. 3041-3056 ◽  
Author(s):  
Liliana Malinovska ◽  
Sonja Kroschwald ◽  
Matthias C. Munder ◽  
Doris Richter ◽  
Simon Alberti
Keyword(s):  
Quality Control ◽  
Molecular Chaperones ◽  
Cellular Response ◽  
Protein Quality ◽  
Acute Stress ◽  
Protein Sorting ◽  
Protein Quality Control ◽  
Normal Growth ◽  
Small Heat Shock Protein ◽  
Misfolded Proteins

Acute stress causes a rapid redistribution of protein quality control components and aggregation-prone proteins to diverse subcellular compartments. How these remarkable changes come about is not well understood. Using a phenotypic reporter for a synthetic yeast prion, we identified two protein-sorting factors of the Hook family, termed Btn2 and Cur1, as key regulators of spatial protein quality control in Saccharomyces cerevisiae. Btn2 and Cur1 are undetectable under normal growth conditions but accumulate in stressed cells due to increased gene expression and reduced proteasomal turnover. Newly synthesized Btn2 can associate with the small heat shock protein Hsp42 to promote the sorting of misfolded proteins to a peripheral protein deposition site. Alternatively, Btn2 can bind to the chaperone Sis1 to facilitate the targeting of misfolded proteins to a juxtanuclear compartment. Protein redistribution by Btn2 is accompanied by a gradual depletion of Sis1 from the cytosol, which is mediated by the sorting factor Cur1. On the basis of these findings, we propose a dynamic model that explains the subcellular distribution of misfolded proteins as a function of the cytosolic concentrations of molecular chaperones and protein-sorting factors. Our model suggests that protein aggregation is not a haphazard process but rather an orchestrated cellular response that adjusts the flux of misfolded proteins to the capacities of the protein quality control system.

scholarly journals Structural basis for translational surveillance by the large ribosomal subunit-associated protein quality control complex

2014 ◽  
Vol 111 (45) ◽  
pp. 15981-15986 ◽  
Author(s):  
Dmitry Lyumkis ◽  
Dario Oliveira dos Passos ◽  
Erich B. Tahara ◽  
Kristofor Webb ◽  
Eric J. Bennett ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Ribosomal Subunit ◽  
Protein Quality Control ◽  
Structural Basis ◽  
Large Ribosomal Subunit ◽  
Control Complex

scholarly journals The ribosome-bound quality control complex remains associated to aberrant peptides during their proteasomal targeting and interacts with Tom1 to limit protein aggregation

2017 ◽  
Vol 28 (9) ◽  
pp. 1165-1176 ◽  
Author(s):  
Quentin Defenouillère ◽  
Abdelkader Namane ◽  
John Mouaikel ◽  
Alain Jacquier ◽  
Micheline Fromont-Racine
Keyword(s):  
Quality Control ◽  
Protein Aggregation ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Translation Termination ◽  
E3 Ubiquitin Ligase ◽  
Protein Quality Control ◽  
Control Mechanisms ◽  
Ubiquitin Ligase Activity ◽  
Control Complex

Protein quality control mechanisms eliminate defective polypeptides to ensure proteostasis and to avoid the toxicity of protein aggregates. In eukaryotes, the ribosome-bound quality control (RQC) complex detects aberrant nascent peptides that remain stalled in 60S ribosomal particles due to a dysfunction in translation termination. The RQC complex polyubiquitylates aberrant polypeptides and recruits a Cdc48 hexamer to extract them from 60S particles in order to escort them to the proteasome for degradation. Whereas the steps from stalled 60S recognition to aberrant peptide polyubiquitylation by the RQC complex have been described, the mechanism leading to proteasomal degradation of these defective translation products remains unknown. We show here that the RQC complex also exists as a ribosome-unbound complex during the escort of aberrant peptides to the proteasome. In addition, we identify a new partner of this light version of the RQC complex, the E3 ubiquitin ligase Tom1. Tom1 interacts with aberrant nascent peptides and is essential to limit their accumulation and aggregation in the absence of Rqc1; however, its E3 ubiquitin ligase activity is not required. Taken together, these results reveal new roles for Tom1 in protein quality control, aggregate prevention, and, therefore, proteostasis maintenance.

scholarly journals Deubiquitinases USP20/33 promote the biogenesis of tail-anchored membrane proteins

2021 ◽  
Vol 220 (5) ◽  
Author(s):  
Jacob A. Culver ◽  
Malaiyalam Mariappan
Keyword(s):  
Quality Control ◽  
Membrane Proteins ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Proteasomal Degradation ◽  
Transmembrane Domains ◽  
Misfolded Proteins ◽  
Hydrophobic Membrane ◽  
Cytosolic Protein ◽  
Ta Proteins

Numerous proteins that have hydrophobic transmembrane domains (TMDs) traverse the cytosol and posttranslationally insert into cellular membranes. It is unclear how these hydrophobic membrane proteins evade recognition by the cytosolic protein quality control (PQC), which typically recognizes exposed hydrophobicity in misfolded proteins and marks them for proteasomal degradation by adding ubiquitin chains. Here, we find that tail-anchored (TA) proteins, a vital class of membrane proteins, are recognized by cytosolic PQC and are ubiquitinated as soon as they are synthesized in cells. Surprisingly, the ubiquitinated TA proteins are not routed for proteasomal degradation but instead are handed over to the targeting factor, TRC40, and delivered to the ER for insertion. The ER-associated deubiquitinases, USP20 and USP33, remove ubiquitin chains from TA proteins after their insertion into the ER. Thus, our data suggest that deubiquitinases rescue posttranslationally targeted membrane proteins that are inappropriately ubiquitinated by PQC in the cytosol.

Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates

2021 ◽  
pp. 153537022199981
Author(s):  
Chamithi Karunanayake ◽  
Richard C Page
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Structural Features ◽  
Cellular Protein ◽  
Mechanisms Of Action ◽  
Control Mechanisms ◽  
Nucleotide Exchange ◽  
Domain Organization ◽  
Nucleotide Exchange Factors

The chaperone heat shock protein 70 (Hsp70) and its network of co-chaperones serve as a central hub of cellular protein quality control mechanisms. Domain organization in Hsp70 dictates ATPase activity, ATP dependent allosteric regulation, client/substrate binding and release, and interactions with co-chaperones. The protein quality control activities of Hsp70 are classified as foldase, holdase, and disaggregase activities. Co-chaperones directly assisting protein refolding included J domain proteins and nucleotide exchange factors. However, co-chaperones can also be grouped and explored based on which domain of Hsp70 they interact. Here we discuss how the network of cytosolic co-chaperones for Hsp70 contributes to the functions of Hsp70 while closely looking at their structural features. Comparison of domain organization and the structures of co-chaperones enables greater understanding of the interactions, mechanisms of action, and roles played in protein quality control.

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