A dual task for the Xbp1-responsive OS-9 variants in the mammalian endoplasmic reticulum - Inhibiting secretion of misfolded protein conformers and enhancing their disposal

Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2008; 283(24):16446-54. DOI: 10.1074/jbc.M802272200
Source: PubMed


Normally, non-native polypeptides are not transported through the secretory pathway. Rather, they are translocated from the endoplasmic reticulum (ER) lumen into the cytosol where they are degraded by proteasomes. Here we characterize the function in ER quality control of two proteins derived from alternative splicing of the OS-9 gene. OS-9.1 and OS-9.2 are ubiquitously expressed in human tissues and are amplified in tumors. They are transcriptionally induced upon activation of the Ire1/Xbp1 ER-stress pathway. OS-9 variants do not associate with folding-competent proteins. Rather, they selectively bind folding-defective ones thereby inhibiting transport of non-native conformers through the secretory pathway. The intralumenal level of OS-9.1 and OS-9.2 inversely correlates with the fraction of a folding-defective glycoprotein, the Null(hong kong) (NHK) variant of alpha1-antitrypsin that escapes retention-based ER quality control. OS-9 up-regulation does not affect NHK disposal, but reduction of the intralumenal level of OS-9.1 and OS-9.2 substantially delays disposal of this model substrate. OS-9.1 and OS-9.2 also associate transiently with non-glycosylated folding-defective proteins, but association is unproductive. Finally, OS-9 activity does not require an intact mannose 6-P homology domain. Thus, OS-9.1 and OS-9.2 play a dual role in mammalian ER quality control: first as crucial retention factors for misfolded conformers, and second as promoters of protein disposal from the ER lumen.

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    • "Afterward the proteins are translocated to the cytosol and degraded by proteasomes. This mannose binding and cleaving may also be performed on nonglycosylated chaperone proteins GRP78 and GRP94 [53] [54] [55]. "
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    ABSTRACT: The folding process is an important step in protein synthesis for the functional shape or conformation of the protein. The endoplasmic reticulum (ER) is the main organelle for the correct folding procedure, which maintains the homeostasis of the organism. This process is normally well organized under unstressed conditions, whereas it may fail under oxidative and ER stress. The unfolded protein response (UPR) is a defense mechanism that removes the unfolded/misfolded proteins to prevent their accumulation, and two main degradation systems are involved in this defense, including the proteasome and autophagy. Cells decide which mechanism to use according to the type, severity, and duration of the stress. If the stress is too severe and in excess, the capacity of these degradation mechanisms, proteasomal degradation and autophagy, is not sufficient and the cell switches to apoptotic death. Because the accumulation of the improperly folded proteins leads to several diseases, it is important for the body to maintain this balance. Cardiovascular diseases are one of the important disorders related to failure of the UPR. Especially, protection mechanisms and the transition to apoptotic pathways have crucial roles in cardiac failure and should be highlighted in detailed studies to understand the mechanisms involved. This review is focused on the involvement of the proteasome, autophagy, and apoptosis in the UPR and the roles of these pathways in cardiovascular diseases. Copyright © 2014 Elsevier Inc. All rights reserved.
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    • "Mannose removal is achieved using ER mannosidase I (ERmanI), the ER degradation-enhancing α-mannosidase-like proteins (EDEMs) and/or the Golgi-resident protein Man1C1 (Gonzalez et al., 1999; Hirao et al., 2006; Olivari et al., 2006; Hosokawa et al., 2007). Several lectins, OS-9 and XTP3-B, then interact via their MRH domains with the mannose-trimmed proteins, allowing their association with the retrotranslocon (Bernasconi et al., 2008; Christianson et al., 2008; Hosokawa et al., 2008). OS-9 and XTP3-B also associate with different proteases, LONP2 and carboxypeptidase vitellogenic-like protein (CPVL), respectively, suggesting that some substrates may be partially degraded prior to dislocation (Christianson et al., 2012; Olzmann et al., 2013). "
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    ABSTRACT: Endoplasmic reticulum (ER)-associated degradation (ERAD) is a universally important process among eukaryotic cells. ERAD is necessary to preserve cell integrity since the accumulation of defective proteins results in diseases associated with neurological dysfunction, cancer, and infections. This process involves recognition of misfolded or misassembled proteins that have been translated in association with ER membranes. Recognition of ERAD substrates leads to their extraction through the ER membrane (retrotranslocation or dislocation), ubiquitination, and destruction by cytosolic proteasomes. This review focuses on ERAD and its components as well as how viruses use this process to promote their replication and to avoid the immune response.
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    • "Similar to Htm1p and Yos9p, EDEM1 and OS-9 appear to discriminate misfolded proteins from native forms to initiate their turnover [22], [23], [24]. For a few ERAD substrates whose degradation requires EDEM1 and OS-9, the trimmed glycan structure on the substrates was found essential for recognition [23], [24], [25]. However, it is not yet known whether in mammalian cells substrate sorting and targeting towards ERAD requires glycan processing, and if so, whether the processing is carried out by these lectins. "
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    ABSTRACT: Misfolded proteins of the endoplasmic reticulum (ER) are eliminated by the ER-associated degradation (ERAD) in eukaryotes. In S. cerevisiae, ER-resident lectins mediate substrate recognition through bipartite signals consisting of an unfolded local structure and the adjacent glycan. Trimming of the glycan is essential for the directional delivery of the substrates. Whether a similar recognition and delivery mechanism exists in mammalian cells is unknown. In this study, we systematically study the function and substrate specificity of known mammalian ER lectins, including EDEM1/2/3, OS-9 and XTP-3B using the recently identified ERAD substrate sonic hedgehog (SHH), a soluble protein carrying a single N-glycan, as well as its nonglycosylated mutant N278A. Efficient ERAD of N278A requires the core processing complex of HRD1, SEL1L and p97, similar to the glycosylated SHH. While EDEM2 was required for ERAD of both glycosylated and non-glycosylated SHHs, EDEM3 was only necessary for glycosylated SHH and EDEM1 was dispensable for both. Degradation of SHH and N278A also required OS-9, but not the related lectin XTP3-B. Robust interaction of both EDEM2 and OS-9 with a non-glycosylated SHH variant indicates that the misfolded polypeptide backbone, rather than a glycan signature, functions as the predominant signal for recognition for ERAD. Notably, SHH-N278A is the first nonglycosylated substrate to require EDEM2 for recognition and targeting for ERAD. EDEM2 also interacts with calnexin and SEL1L, suggesting a potential avenue by which misfolded glycoproteins may be shunted towards SEL1L and ERAD rather than being released into the secretory pathway. Thus, ER lectins participate in the recognition and delivery of misfolded ER substrates differently in mammals, with an underlying mechanism distinct from that of S. cerevisiae.
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