Sel1L‐Hrd1‐Mediated OS9 Degradation During Endoplasmic Reticulum Stress

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Misfolded or unfolded proteins generated by inefficient protein folding or ER stress is translocated from the ER to cytosol for proteasome degradation, a process termed endoplasmic reticulum associated degradation (ERAD). OS9, a lectin protein, has been shown to deliver misfolded or unfolded glycoproteins to the most conserved ERAD complexes in the mammalian system, the Sel1L-Hrd1 ERAD complex (Mehnert et al., 2010). Our study on OS9 shows that despite being an effector of the complex, OS9 itself is degraded by the same complex in response to ER stress. OS9 protein level decreases drastically upon the treatment of Tunicamycin (TM), Thapsigargin (Tg) or Dithiothreitol (DTT) . The addition of MG132 completely blocked the degradation, showing OS9 is degraded by proteasome. We then show the degradation of OS9 is abolished in Hrd1 knock-out (Hrd1-/- ) MEF cells, and significantly attenuated in Sel1L-/- cells when cells were treated with 6hr of cycloheximide (CHX), suggesting both Sel1L and Hrd1 are required for the degradation of OS9, but Hrd1 plays a more important role in the process. We also find that the protein level of OS9 is significantly higher in Sel1L-inducible knock out (IKO) mice than in WT mice, confirming that OS9 is degraded by Sel1L-Hrd1 complex in vivo. Using co-immunoprecipitation (CO-IP), we find that Sel1L associates with OS9 in a glycosylation independent manner and that it can be ubiquitinated by overexpressed Hrd1. In addition, our data suggest the protein stability of OS9 is mediated through the XBP1-Hrd1 axis. These data suggest that OS9 is degraded through the Sel1L-Hrd1 complex under ER stress. Not only does this study identifies a potential endogenous substrate of the Sel1L-Hrd1 complex, given the fact that OS9 is an effector of the complex, this study may also provide insights into a possible self-regulatory mechanism of the complex through regulating OS9.
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Endoplasmic Reticulum Stress
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