Mitochondrial quality control by the ubiquitin–proteasome system

2011 ◽  
Vol 39 (5) ◽  
pp. 1509-1513 ◽  
Author(s):  
Eric B. Taylor ◽  
Jared Rutter
Keyword(s):  
Quality Control ◽  
Ubiquitin Ligase ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Quality Control ◽  
Ubiquitinated Proteins ◽  
Ubiquitin Proteasome

Mitochondria perform multiple functions critical to the maintenance of cellular homoeostasis and their dysfunction leads to disease. Several lines of evidence suggest the presence of a MAD (mitochondria-associated degradation) pathway that regulates mitochondrial protein quality control. Internal mitochondrial proteins may be retrotranslocated to the OMM (outer mitochondrial membrane), multiple E3 ubiquitin ligases reside at the OMM and inhibition of the proteasome causes accumulation of ubiquitinated proteins at the OMM. Reminiscent of ERAD [ER (endoplasmic reticulum)-associated degradation], Cdc48 (cell division cycle 42)/p97 is recruited to stressed mitochondria, extracts ubiquitinated proteins from the OMM and presents ubiquitinated proteins to the proteasome for degradation. Recent research has provided mechanistic insights into the interaction of the UPS (ubiquitin–proteasome system) with the OMM. In yeast, Vms1 [VCP (valosin-containing protein) (p97)/Cdc48-associated mitochondrial-stress-responsive 1] protein recruits Cdc48/p97 to the OMM. In mammalian systems, the E3 ubiquitin ligase parkin regulates the recruitment of Cdc48/p97 to mitochondria, subsequent mitochondrial protein degradation and mitochondrial autophagy. Disruption of the Vms1 or parkin systems results in the hyper-accumulation of ubiquitinated proteins at mitochondria and subsequent mitochondrial dysfunction. The emerging MAD pathway is important for the maintenance of cellular and therefore organismal viability.

scholarly journals A conserved quality-control pathway that mediates degradation of unassembled ribosomal proteins

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Min-Kyung Sung ◽  
Tanya R Porras-Yakushi ◽  
Justin M Reitsma ◽  
Ferdinand M Huber ◽  
Michael J Sweredoski ◽  
...  
Keyword(s):  
Quality Control ◽  
Ribosomal Protein ◽  
Ubiquitin Ligase ◽  
Ribosomal Proteins ◽  
Protein Quality ◽  
Ubiquitin Proteasome System ◽  
Protein Homeostasis ◽  
System Quality ◽  
Ubiquitin Proteasome ◽  
E2 Enzymes

Overproduced yeast ribosomal protein (RP) Rpl26 fails to assemble into ribosomes and is degraded in the nucleus/nucleolus by a ubiquitin-proteasome system quality control pathway comprising the E2 enzymes Ubc4/Ubc5 and the ubiquitin ligase Tom1. tom1 cells show reduced ubiquitination of multiple RPs, exceptional accumulation of detergent-insoluble proteins including multiple RPs, and hypersensitivity to imbalances in production of RPs and rRNA, indicative of a profound perturbation to proteostasis. Tom1 directly ubiquitinates unassembled RPs primarily via residues that are concealed in mature ribosomes. Together, these data point to an important role for Tom1 in normal physiology and prompt us to refer to this pathway as ERISQ, for excess ribosomal protein quality control. A similar pathway, mediated by the Tom1 homolog Huwe1, restricts accumulation of overexpressed hRpl26 in human cells. We propose that ERISQ is a key element of the quality control machinery that sustains protein homeostasis and cellular fitness in eukaryotes.

scholarly journals TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

2021 ◽  
Author(s):  
Xu Zhou ◽  
Xiongjin Chen ◽  
Tingting Hong ◽  
Miaoping Zhang ◽  
Yujie Cai ◽  
...  
Keyword(s):  
Quality Control ◽  
Cognitive Impairment ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Research Progress ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

Protein Quality Control in Neurodegeneration and Neuroprotection

2020 ◽  
pp. 1-24
Author(s):  
Yasmeena Akhter ◽  
Jahangir Nabi ◽  
Hinna Hamid ◽  
Nahida Tabassum ◽  
Faheem Hyder Pottoo ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Disorders ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Security System ◽  
Conformational Disorders ◽  
Ubiquitin Proteasome ◽  
Multi Level

Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.

Msp1/ATAD1 in Protein Quality Control and Regulation of Synaptic Activities

2020 ◽  
Vol 36 (1) ◽  
pp. 141-164
Author(s):  
Lan Wang ◽  
Peter Walter
Keyword(s):  
Quality Control ◽  
Mitochondrial Membrane ◽  
Protein Import ◽  
Protein Quality ◽  
Atp Hydrolysis ◽  
Mitochondrial Protein ◽  
Neurotransmitter Receptors ◽  
Functional Specialization ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Protein Import

Mitochondrial function depends on the efficient import of proteins synthesized in the cytosol. When cells experience stress, the efficiency and faithfulness of the mitochondrial protein import machinery are compromised, leading to homeostatic imbalances and damage to the organelle. Yeast Msp1 (mitochondrial sorting of proteins 1) and mammalian ATAD1 (ATPase family AAA domain–containing 1) are orthologous AAA proteins that, fueled by ATP hydrolysis, recognize and extract mislocalized membrane proteins from the outer mitochondrial membrane. Msp1 also extracts proteins that have become stuck in the import channel. The extracted proteins are targeted for proteasome-dependent degradation or, in the case of mistargeted tail-anchored proteins, are given another chance to be routed correctly. In addition, ATAD1 is implicated in the regulation of synaptic plasticity, mediating the release of neurotransmitter receptors from postsynaptic scaffolds to allow their trafficking. Here we discuss how structural and functional specialization imparts the unique properties that allow Msp1/ATAD1 ATPases to fulfill these diverse functions and also highlight outstanding questions in the field.

scholarly journals The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover

2011 ◽  
Vol 22 (3) ◽  
pp. 291-300 ◽  
Author(s):  
Shan Xu ◽  
Guihong Peng ◽  
Yang Wang ◽  
Shengyun Fang ◽  
Mariusz Karbowski
Keyword(s):  
Mitochondrial Membrane ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Outer Mitochondrial Membrane ◽  
Aaa Atpase ◽  
Associated Proteins ◽  
Ubiquitin Proteasome ◽  
Molecular Components

Recent studies have revealed a role for the ubiquitin/proteasome system in the regulation and turnover of outer mitochondrial membrane (OMM)-associated proteins. Although several molecular components required for this process have been identified, the mechanism of proteasome-dependent degradation of OMM-associated proteins is currently unclear. We show that an AAA-ATPase, p97, is required for the proteasomal degradation of Mcl1 and Mfn1, two unrelated OMM proteins with short half-lives. A number of biochemical assays, as well as imaging of changes in localization of photoactivable GFP-fused Mcl1, revealed that p97 regulates the retrotranslocation of Mcl1 from mitochondria to the cytosol, prior to, or concurrent with, proteasomal degradation. Mcl1 retrotranslocation from the OMM depends on the activity of the ATPase domain of p97. Furthermore, p97-mediated retrotranslocation of Mcl1 can be recapitulated in vitro, confirming a direct mitochondrial role for p97. Our results establish p97 as a novel and essential component of the OMM-associated protein degradation pathway.

scholarly journals The Loss of Mitochondrial Quality Control in Diabetic Kidney Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Wenni Dai ◽  
Hengcheng Lu ◽  
Yinyin Chen ◽  
Danyi Yang ◽  
Lin Sun ◽  
...  
Keyword(s):  
Quality Control ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Protein Quality ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Protein ◽  
Eukaryotic Cell ◽  
Mitochondrial Quality Control ◽  
Diabetic Kidney

Diabetic kidney disease (DKD) is the predominant complication of diabetes mellitus (DM) and the leading cause of chronic kidney disease and end-stage renal disease worldwide, which are major risk factors for death. The pathogenesis of DKD is very complicated, including inflammation, autophagy impairment, oxidative stress, and so on. Recently, accumulating evidence suggests that the loss of mitochondrial quality control exerts critical roles in the progression of DKD. Mitochondria are essential for eukaryotic cell viability but are extremely vulnerable to damage. The mechanisms of mitochondrial quality control act at the molecular level and the organelle level, including mitochondrial dynamics (fusion and fission), mitophagy, mitochondrial biogenesis, and mitochondrial protein quality control. In this review, we summarize current knowledge of the role of disturbances in mitochondrial quality control in the pathogenesis of DKD and provide potential insights to explore how to delay the onset and development of DKD.

scholarly journals Disease-linked mutations trigger exposure of a protein quality control degron in the DHFR protein

2021 ◽  
Author(s):  
Caroline Kampmeyer ◽  
Sven Larsen-Ledet ◽  
Morten Rose Wagnkilde ◽  
Mathias Michelsen ◽  
Henriette K. M. Iversen ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Yeast Cells ◽  
Cell Cycle Regulators ◽  
Missense Variants ◽  
Hydrogen Deuterium ◽  
Ubiquitin Proteasome ◽  
Protein Ligases

Degrons are short stretches of amino acids or structural motifs that are embedded in proteins. They mediate recognition by E3 ubiquitin-protein ligases and thus confer protein degradation via the ubiquitin-proteasome system. Well-described degrons include the N-degrons, destruction boxes, and the PIP degrons, which mediate the controlled degradation of various proteins including signaling components and cell cycle regulators. In comparison, the so-called protein quality control (PQC) degrons that mediate the degradation of structurally destabilized or misfolded proteins are not well described. Here, we show that disease-linked DHFR missense variants are structurally destabilized and chaperone-dependent proteasome targets. We systematically mapped regions within DHFR to assess those that act as cytosolic PQC degrons in yeast cells. Two regions, DHFR-Deg13-36 (here Deg1) and DHFR-Deg61-84 (here Deg2), act as degrons and conferred degradation to unrelated fusion partners. The proteasomal turnover of Deg2 was dependent on the molecular chaperone Hsp70. Structural analyses by NMR and hydrogen/deuterium exchange revealed that Deg2 is buried in wild-type DHFR, but becomes transiently exposed in the disease-linked missense variants.

scholarly journals Selective autophagic clearance of protein aggregates is mediated by the autophagy receptor, TAX1BP1

2019 ◽  
Author(s):  
Shireen A. Sarraf ◽  
Hetal V. Shah ◽  
Gil Kanfer ◽  
Michael E. Ward ◽  
Richard J. Youle
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Protein Aggregates ◽  
Ubiquitin Proteasome System ◽  
Cellular Homeostasis ◽  
Receptor Proteins ◽  
Proteotoxic Stress ◽  
Polyq Protein ◽  
Ubiquitin Proteasome

AbstractMisfolded protein aggregates can disrupt cellular homeostasis and cause toxicity, a hallmark of numerous neurodegenerative diseases. Protein quality control by the ubiquitin proteasome system (UPS) and autophagy is vital for clearance of aggregates and maintenance of cellular homeostasis1. Autophagy receptor proteins bridge the interaction between ubiquitinated proteins and the autophagy machinery allowing selective elimination of cargo2. Aggrephagy is critical to protein quality control, but how aggregates are recognized and targeted for degradation is not well understood. Here we examine the requirements for 5 autophagy receptor proteins: OPTN, NBR1, p62, NDP52, and TAX1BP1 in proteotoxic stress-induced aggregate clearance. Endogenous TAX1BP1 is both recruited to and required for the clearance of stress-induced aggregates while overexpression of TAX1BP1 increases aggregate clearance through autophagy. Furthermore, TAX1BP1 depletion sensitizes cells to proteotoxic stress and Huntington’s disease-linked polyQ proteins, whereas TAX1BP1 overexpression clears cells of polyQ protein aggregates by autophagy. We propose a broad role for TAX1BP1 in the clearance of cytotoxic proteins, thus identifying a new mode of clearance of protein inclusions.

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