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      Interplay of Substrate Retention and Export Signals in Endoplasmic Reticulum Quality Control

      research-article
      1 , 1 , 1 , 2 , *
      PLoS ONE
      Public Library of Science

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          Abstract

          Background

          Endoplasmic reticulum (ER) quality control mechanisms are part of a comprehensive system to manage cell stress. The flux of molecules is monitored to retain folding intermediates and target misfolded molecules to ER-associated degradation (ERAD) pathways. The mechanisms of sorting remain unclear. While some proteins are retained statically, the classical model substrate CPY* is found in COPII transport vesicles, suggesting a retrieval mechanism for retention. However, its management can be even more dynamic. If ERAD is saturated under stress, excess CPY* traffics to the vacuole for degradation. These observations suggest that misfolded proteins might display different signals for their management.

          Methodology/Principal Findings

          Here, we report the existence of a functional ER exit signal in the pro-domain of CPY*. Compromising its integrity causes ER retention through exclusion from COPII vesicles. The signal co-exists with other signals used for retention and degradation. Physiologically, the export signal is important for stress tolerance. Disabling it converts a benign protein into one that is intrinsically cytotoxic.

          Conclusions/Significance

          These data reveal the remarkable interplay between opposing signals embedded within ERAD substrate molecules and the mechanisms that decipher them. Our findings demonstrate the diversity of mechanisms deployed for protein quality control and maintenance of protein homeostasis.

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          Most cited references54

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          One step at a time: endoplasmic reticulum-associated degradation.

          Protein folding in the endoplasmic reticulum (ER) is monitored by ER quality control (ERQC) mechanisms. Proteins that pass ERQC criteria traffic to their final destinations through the secretory pathway, whereas non-native and unassembled subunits of multimeric proteins are degraded by the ER-associated degradation (ERAD) pathway. During ERAD, molecular chaperones and associated factors recognize and target substrates for retrotranslocation to the cytoplasm, where they are degraded by the ubiquitin-proteasome machinery. The discovery of diseases that are associated with ERAD substrates highlights the importance of this pathway. Here, we summarize our current understanding of each step during ERAD, with emphasis on the factors that catalyse distinct activities.
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            COPII: a membrane coat formed by Sec proteins that drive vesicle budding from the endoplasmic reticulum.

            In vitro synthesis of endoplasmic reticulum-derived transport vesicles has been reconstituted with washed membranes and three soluble proteins (Sar1p, Sec13p complex, and Sec23p complex). Vesicle formation requires GTP but can be driven by nonhydrolyzable analogs such as GMP-PNP. However, GMP-PNP vesicles fail to target and fuse with the Golgi complex whereas GTP vesicles are functional. All the cytosolic proteins required for vesicle formation are retained on GMP-PNP vesicles, while Sar1p dissociates from GTP vesicles. Thin section electron microscopy of purified preparations reveals a uniform population of 60-65 nm vesicles with a 10 nm thick electron dense coat. The subunits of this novel coat complex are molecularly distinct from the constituents of the nonclathrin coatomer involved in intra-Golgi transport. Because the overall cycle of budding driven by these two types of coats appears mechanistically similar, we propose that the coat structures be called COPI and COPII.
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              A time-dependent phase shift in the mammalian unfolded protein response.

              Unfolded or misfolded proteins in the endoplasmic reticulum (ER) must be refolded or degraded to maintain homeostasis of the ER. The ATF6 and IRE1-XBP1 pathways are important for the refolding process in mammalian cells; activation of these transcriptional programs culminates in induction of ER-localized molecular chaperones and folding enzymes. We show here that degradation of misfolded glycoprotein substrates requires transcriptional induction of EDEM (ER degradation-enhancing alpha-mannosidase-like protein), and that this is mediated specifically by IRE1-XBP1 and not by ATF6. As XBP1 is produced after ATF6 activation, our results reveal a time-dependent transition in the mammalian unfolded protein response: an ATF6-mediated unidirectional phase (refolding only) is followed by an XBP1-mediated bidirectional phase (refolding plus degradation) as the response progresses.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                24 November 2010
                : 5
                : 11
                : e15532
                Affiliations
                [1 ]Temasek Life Sciences Laboratory, National University of Singapore, Singapore, Singapore
                [2 ]Department of Biological Sciences, National University of Singapore, Singapore, Singapore
                Universidade de São Paulo, Brazil
                Author notes

                Conceived and designed the experiments: SK CLH DTWN. Performed the experiments: SK CLH. Analyzed the data: SK CLH DTWN. Contributed reagents/materials/analysis tools: SK CLH DTWN. Wrote the paper: SK DTWN.

                [¤]

                Current address: Academia Sinica, Taipei, Taiwan

                Article
                PONE-D-10-00493
                10.1371/journal.pone.0015532
                2991357
                21151492
                d51062f3-b3a0-452e-b590-b9f814ee241f
                Kawaguchi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 11 August 2010
                : 5 October 2010
                Page count
                Pages: 14
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Physiological Processes
                Homeostasis
                Cell Physiology
                Biochemistry
                Glycobiology
                Glycoproteins
                Proteins
                Chaperone Proteins
                Genetics
                Genetic Mutation
                Molecular Genetics
                Model Organisms
                Yeast and Fungal Models
                Saccharomyces Cerevisiae
                Molecular Cell Biology
                Cellular Structures
                Subcellular Organelles
                Signal Transduction
                Signaling in Cellular Processes
                Cellular Stress Responses
                Membranes and Sorting

                Uncategorized
                Uncategorized

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