15
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      The ART-Rsp5 ubiquitin ligase network comprises a plasma membrane quality control system that protects yeast cells from proteotoxic stress

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Secretory cargo that cannot fold properly in the ER are selectively targeted for removal by a well-studied ER-associated degradation pathway, or ERAD. In contrast, very little is known about post-ER quality control mechanisms for damaged or misfolded integral membrane proteins. Here we describe a quality control function of the Rsp5-ART ubiquitin ligase adaptor network that functions to protect plasma membrane (PM) integrity. Failure to mediate this protective response during heat stress leads to toxic accumulation of misfolded integral membrane proteins at the cell surface, which causes loss of PM integrity and cell death. Thus, the Rsp5-ART network comprises a PM quality control system that works together with sequential quality control pathways in the ER and Golgi to (i) target the degradation of proteins that have exceeded their functional lifetime due to damage and/or misfolding and (ii) limit the toxic accumulation of specific proteins at the cell surface during proteotoxic stress.

          DOI: http://dx.doi.org/10.7554/eLife.00459.001

          eLife digest

          Cells have evolved elaborate mechanisms for the detection of misfolded or damaged proteins, and for targeting their degradation. Since the accumulation of misfolded proteins is toxic to the cell, these protein quality control systems are critical for the maintenance of normal cellular function over the lifetime of an organism. The breakdown of this quality control correlates with the progression of neurodegenerative disorders including Alzheimer's, Huntington's and Parkinson's disease. Normal function of the protein quality control machinery can also cause disease: this is the case with channelopathies such as cystic fibrosis, in which mutant ion channels are targeted for degradation and therefore cannot function correctly at the cell surface. Understanding how protein quality control systems recognize misfolded proteins and target their degradation, and designing ways to stabilize or destabilize specific targets, particularly at the cell surface, could thus lead to the development of new therapeutic strategies.

          While protein quality control mechanisms in the cytosol and endoplasmic reticulum (ER) have been studied extensively, much less is known about quality control of integral membrane proteins after they exit the ER. Maintaining the quality of cell surface proteins impacts many critical biological functions including nutrient uptake, signaling and the functioning of specialized surface structures such as cell junctions.

          Here, Zhao et al. describe a new quality control mechanism that prevents misfolded proteins from accumulating in the plasma membrane. Building upon earlier work describing a network of adaptor proteins (called ARTs) for the Rsp5 ubiquitin ligase, Zhao et al. show that subjecting cells to proteotoxic stress, particularly thermal stress, triggers ART-Rsp5-mediated clearance of misfolded plasma membrane proteins. When ART-Rsp5-mediated clearance is abrogated, misfolded proteins accumulate at the cell surface, resulting in a rapid loss of cellular integrity. In the brain, such proteotoxicity can lead to cell death and neurodegeneration, thereby highlighting the importance of this plasma membrane quality control system.

          DOI: http://dx.doi.org/10.7554/eLife.00459.002

          Related collections

          Most cited references23

          • Record: found
          • Abstract: found
          • Article: not found

          Dissecting the architecture of a quantitative trait locus in yeast.

          Most phenotypic diversity in natural populations is characterized by differences in degree rather than in kind. Identification of the actual genes underlying these quantitative traits has proved difficult. As a result, little is known about their genetic architecture. The failures are thought to be due to the different contributions of many underlying genes to the phenotype and the ability of different combinations of genes and environmental factors to produce similar phenotypes. This study combined genome-wide mapping and a new genetic technique named reciprocal-hemizygosity analysis to achieve the complete dissection of a quantitative trait locus (QTL) in Saccharomyces cerevisiae. A QTL architecture was uncovered that was more complex than expected. Functional linkages both in cis and in trans were found between three tightly linked quantitative trait genes that are neither necessary nor sufficient in isolation. This arrangement of alleles explains heterosis (hybrid vigour), the increased fitness of the heterozygote compared with homozygotes. It also demonstrates a deficiency in current approaches to QTL dissection with implications extending to traits in other organisms, including human genetic diseases.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Arrestin-related ubiquitin-ligase adaptors regulate endocytosis and protein turnover at the cell surface.

            The diversity of plasma membrane (PM) proteins presents a challenge for the achievement of cargo-specific regulation of endocytosis. Here, we describe a family of proteins in yeast (ARTs, for arrestin-related trafficking adaptors) that function by targeting specific PM proteins to the endocytic system. Two members (Art1 and Art2) of the family were discovered in chemical-genetic screens, and they direct downregulation of distinct amino acid transporters triggered by specific stimuli. Sequence analysis revealed a total of nine ART family members in yeast. In addition to similarity to arrestins, the ARTs each contain multiple PY motifs. These motifs are required for recruitment of the Rsp5/Nedd4-like ubiquitin ligase, which modifies the cargoes as well as the ARTs. As a result, ubiquitinated cargoes are internalized and targeted to the vacuole (lysosome) for degradation. We propose that ARTs provide a cargo-specific quality-control pathway that mediates endocytic downregulation by coupling Rsp5/Nedd4 to diverse plasma membrane proteins.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation.

              The folding of both wild-type and mutant forms of the cystic-fibrosis transmembrane-conductance regulator (CFTR), a plasma-membrane chloride-ion channel, is inefficient. Most nascent CFTR is retained in the endoplasmic reticulum and degraded by the ubiquitin proteasome pathway. Aberrant folding and defective trafficking of CFTRDeltaF508 is the principal cause of cystic fibrosis, but how the endoplasmic-reticulum quality-control system targets CFTR for degradation remains unknown. CHIP is a cytosolic U-box protein that interacts with Hsc70 through a set of tetratricorepeat motifs. The U-box represents a modified form of the ring-finger motif that is found in ubiquitin ligases and that defines the E4 family of polyubiquitination factors. Here we show that CHIP functions with Hsc70 to sense the folded state of CFTR and targets aberrant forms for proteasomal degradation by promoting their ubiquitination. The U-box appeared essential for this process because overexpresion of CHIPDeltaU-box inhibited the action of endogenous CHIP and blocked CFTR ubiquitination and degradation. CHIP is a co-chaperone that converts Hsc70 from a protein-folding machine into a degradation factor that functions in endoplasmic-reticulum quality control.
                Bookmark

                Author and article information

                Contributors
                Role: Reviewing editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                16 April 2013
                2013
                : 2
                : e00459
                Affiliations
                [1 ]Weill Institute of Cell and Molecular Biology, Cornell University , Ithaca, United States
                California Institute of Technology , United States
                California Institute of Technology , United States
                Author notes
                [* ]For correspondence: sde26@ 123456cornell.edu
                [†]

                These authors contributed equally to this work.

                Article
                00459
                10.7554/eLife.00459
                3628405
                23599894
                28909f33-7a77-4ceb-879e-c82811d5c021
                Copyright © 2013, Zhao et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 13 December 2012
                : 13 March 2013
                Funding
                Funded by: NIH K99 Pathway to Independence Award
                Award ID: 1K99GM101077
                Award Recipient :
                Funded by: Cornell University Research Grant
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Cell Biology
                Custom metadata
                Ubiquitin ligase adaptors target the selective clearance of misfolded plasma membrane proteins.

                Life sciences
                endocytosis,membrane traffic,ubiquitin,quality control,proteostasis,s. cerevisiae
                Life sciences
                endocytosis, membrane traffic, ubiquitin, quality control, proteostasis, s. cerevisiae

                Comments

                Comment on this article