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Recent Insights Into the Role of the Ubiquitin System in Cellular Protein Quality Control

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 15220

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Special Issue Editors

Prof. Tommer Ravid

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Guest Editor

Department of Biological Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat-Ram, Jerusalem 91904, Israel
Interests: ubiquitin-proteasome system; protein quality control; ERAD; yeast genetics & proteomics
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Rasmus Hartmann-Petersen

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Guest Editor

Department of Biology, The Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, Denmark
Interests: protein quality control; the ubiquitin-proteasome system; molecular chaperones; protein misfolding; genetic diseases

Special Issue Information

Dear Colleagues,

Post-translational modification by ubiquitin and ubiquitin-like (UBL) molecules plays a crucial role in multiple cellular pathways, including protein quality control (PQC). Unlike regulated ubiquitin conjugation, in which E3 ubiquitin-protein ligases recognize a small set of specific substrates, ubiquitylation in PQC must accommodate a broad range of different substrates and accordingly PQC ubiquitin ligases appear highly redundant. To perform their function, these ligases cooperate with molecular chaperones that keep misfolded substrates in a soluble form to enable their ubiquitylation, deliver substrates to the ubiquitylation machinery, and shuttle ubiquitylated proteins to the proteasome. When proteolysis fails, misfolded substrates are condensed into inclusion bodies, with the aid of designated chaperones, that may be targeted to autophagy. Failure of the PQC proteolytic system may have adverse consequences to cell viability, underlined by early- and late-onset proteopathies.

How the ubiquitin system is involved in PQC triage decisions is yet not fully understood, but clearly depends on key related factors, such as a protein’s folding state and aggregation propensity as well as availability of the PQC network and environmental conditions. This issue aims to introduce the state of the art in ubiquitin/UBL mediated PQC and highlight key finding, in order to stimulate the build-up of an open community with mutual research interests.

Prof. Dr. Tommer Ravid
Prof. Dr. Rasmus Hartmann-Petersen
Guest Editors

Manuscript Submission Information

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Keywords

ubiquitin
proteolysis
protein quality control
molecular chaperones
autophagy, inclusion bodies

Published Papers (4 papers)

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Research

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14 pages, 3473 KiB

Open AccessArticle

The San1 Ubiquitin Ligase Avidly Recognizes Misfolded Proteins through Multiple Substrate Binding Sites

by Rebeca Ibarra, Heather R. Borror, Bryce Hart, Richard G. Gardner and Gary Kleiger

Biomolecules 2021, 11(11), 1619; https://doi.org/10.3390/biom11111619 - 2 Nov 2021

Cited by 3 | Viewed by 1865

Abstract

Cellular homeostasis depends on robust protein quality control (PQC) pathways that discern misfolded proteins from functional ones in the cell. One major branch of PQC involves the controlled degradation of misfolded proteins by the ubiquitin-proteasome system. Here ubiquitin ligases must recognize and bind to misfolded proteins with sufficient energy to form a complex and with an adequate half-life to achieve poly-ubiquitin chain formation, the signal for protein degradation, prior to its dissociation from the ligase. It is not well understood how PQC ubiquitin ligases accomplish these tasks. Employing a fully reconstituted enzyme and substrate system to perform quantitative biochemical experiments, we demonstrate that the yeast PQC ubiquitin ligase San1 contains multiple substrate binding sites along its polypeptide chain that appear to display specificity for unique misfolded proteins. The results are consistent with a model where these substrate binding sites enable San1 to bind to misfolded substrates avidly, resulting in high affinity ubiquitin ligase-substrate complexes. Full article

(This article belongs to the Special Issue Recent Insights Into the Role of the Ubiquitin System in Cellular Protein Quality Control)

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11 pages, 2151 KiB

Open AccessArticle

An Arsenite Relay between PSMD14 and AIRAP Enables Revival of Proteasomal DUB Activity

by Sigalit Sukenik, Ilana Braunstein and Ariel Stanhill

Biomolecules 2021, 11(9), 1317; https://doi.org/10.3390/biom11091317 - 6 Sep 2021

Cited by 2 | Viewed by 2141

Abstract

Maintaining 26S proteasome activity under diverse physiological conditions is a fundamental requirement in order to maintain cellular proteostasis. Several quantitative and qualitative mechanisms have evolved to ensure that ubiquitin–proteasome system (UPS) substrates do not accumulate and lead to promiscuous protein–protein interactions that, in turn, lead to cellular malfunction. In this report, we demonstrate that Arsenite Inducible Regulatory Particle-Associate Protein (AIRAP), previously reported as a proteasomal adaptor required for maintaining proteasomal flux during arsenite exposure, can directly bind arsenite molecules. We further show that arsenite inhibits Psmd14/Rpn11 metalloprotease deubiquitination activity by substituting zinc binding to the MPN/JAMM domain. The proteasomal adaptor AIRAP is able to directly relieve PSMD14/Rpn11 inhibition. A possible metal relay between arsenylated PSMD14/Rpn11 and AIRAP may serve as a cellular mechanism that senses proteasomal inhibition to restore Psmd14/Rpn11 activity. Full article

(This article belongs to the Special Issue Recent Insights Into the Role of the Ubiquitin System in Cellular Protein Quality Control)

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Review

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24 pages, 2494 KiB

Open AccessEditor’s ChoiceReview

Ubiquitin Ligase Redundancy and Nuclear-Cytoplasmic Localization in Yeast Protein Quality Control

by Carolyn Allain Breckel and Mark Hochstrasser

Biomolecules 2021, 11(12), 1821; https://doi.org/10.3390/biom11121821 - 3 Dec 2021

Cited by 16 | Viewed by 4214

Abstract

The diverse functions of proteins depend on their proper three-dimensional folding and assembly. Misfolded cellular proteins can potentially harm cells by forming aggregates in their resident compartments that can interfere with vital cellular processes or sequester important factors. Protein quality control (PQC) pathways are responsible for the repair or destruction of these abnormal proteins. Most commonly, the ubiquitin-proteasome system (UPS) is employed to recognize and degrade those proteins that cannot be refolded by molecular chaperones. Misfolded substrates are ubiquitylated by a subset of ubiquitin ligases (also called E3s) that operate in different cellular compartments. Recent research in Saccharomyces cerevisiae has shown that the most prominent ligases mediating cytoplasmic and nuclear PQC have overlapping yet distinct substrate specificities. Many substrates have been characterized that can be targeted by more than one ubiquitin ligase depending on their localization, and cytoplasmic PQC substrates can be directed to the nucleus for ubiquitylation and degradation. Here, we review some of the major yeast PQC ubiquitin ligases operating in the nucleus and cytoplasm, as well as current evidence indicating how these ligases can often function redundantly toward substrates in these compartments. Full article

(This article belongs to the Special Issue Recent Insights Into the Role of the Ubiquitin System in Cellular Protein Quality Control)

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16 pages, 3067 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Targeting of Native Proteins to the Endoplasmic Reticulum-Associated Degradation (ERAD) Pathway: An Expanding Repertoire of Regulated Substrates

by Deepa Kumari and Jeffrey L. Brodsky

Biomolecules 2021, 11(8), 1185; https://doi.org/10.3390/biom11081185 - 11 Aug 2021

Cited by 18 | Viewed by 5989

Abstract

All proteins are subject to quality control processes during or soon after their synthesis, and these cellular quality control pathways play critical roles in maintaining homeostasis in the cell and in organism health. Protein quality control is particularly vital for those polypeptides that enter the endoplasmic reticulum (ER). Approximately one-quarter to one-third of all proteins synthesized in eukaryotic cells access the ER because they are destined for transport to the extracellular space, because they represent integral membrane proteins, or because they reside within one of the many compartments of the secretory pathway. However, proteins that mature inefficiently are subject to ER-associated degradation (ERAD), a multi-step pathway involving the chaperone-mediated selection, ubiquitination, and extraction (or “retrotranslocation”) of protein substrates from the ER. Ultimately, these substrates are degraded by the cytosolic proteasome. Interestingly, there is an increasing number of native enzymes and metabolite and solute transporters that are also targeted for ERAD. While some of these proteins may transiently misfold, the ERAD pathway also provides a route to rapidly and quantitatively downregulate the levels and thus the activities of a variety of proteins that mature or reside in the ER. Full article

(This article belongs to the Special Issue Recent Insights Into the Role of the Ubiquitin System in Cellular Protein Quality Control)

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