Our long-term goal is to delineate the molecular mechanisms underlying the maintenance of endoplasmic reticulum (ER) homeostasis by two key quality-control systems in the cell, ER-associated degradation (ERAD) and unfolded protein response (UPR). Recently, we have identified a novel regulator of IRE1?, the most conserved sensor of the UPR (He et al. Dev Cell 2012), and reported the generation and characterization of inducible Sel1L knockout (Sel1LIKO) mouse and cell models (Sun et al. PNAS 2014), a cofactor of the ubiquitin ligase Hrd1 in mammalian ERAD. In the preliminary data of this application, we discovered a unique crosstalk between UPR and ERAD, namely the regulation of IRE1? stability by the Sel1L-Hrd1 ERAD complex. Here we showed that loss of Sel1L-Hrd1 ERAD function leads to a dramatic accumulation of IRE1?protein in various tissues and cell types including pancreas, colon, spleen, adipose tissue, MEFs, macrophages and etc. IRE1? accumulation in the absence of Sel1L is independent of transcriptional regulation, pointing to a post-transcriptional control. Indeed, IRE1? interacts with Sel1L and is significantly stabilized in the absence of Sel1L or Hrd1. Thus, these data point to IRE1? as a misfolding- prone Sel1L-Hrd1 ERAD substrate. Here we propose to test the hypotheses that IRE1? is an ERAD substrate and that the Sel1L-Hrd1 ERAD complex negatively regulates the amplitude of IRE1? signaling by mediating its degradation. Taking advantage of systems and tools that we have generated for both Sel1L ERAD and IRE1?, we will accomplish the following Aims: (1) Determine the biological significance of IRE1? ERAD on IRE1? signaling and cell survival; (2) Determine how misfolded IRE1? protein is recognized and delivered to the Sel1L-Hrd1 ERAD complex; and (3) Elucidate how misfolded IRE1? protein is degraded by the Sel1L-Hrd1 ERAD complex. Successful completion of this study may not only provide key insights into IRE1? and ERAD biology, but also uncover a novel regulatory mechanism for IRE1? signaling. This study will provide an unprecedented opportunity to investigate the complicated mechanism of ERAD using an endogenous substrate with great physiological significance, thus exerting a powerful influence on our views of physiological ERAD and UPR biology.

Public Health Relevance

Disturbance of ER homeostasis has been implicated in numerous human diseases ranging from metabolic disorders to neurodegeneration. Our study aspires to delineate the mechanisms underlying the biology of two key ER quality-control machineries and their crosstalk, thus have significant therapeutic implications for human health. IRE1? and the Sel1L-Hrd1 complex represent the most conserved branch of the unfolded protein response (UPR) and endoplasmic reticulum-associated degradation (ERAD), respectively, two principle quality- control mechanisms that ensure homeostasis in the ER. We recently discovered that IRE1? is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. The goal of this application is to establish the molecular mechanism underlying IRE1? ERAD and gain comprehensive insights into its physiological significance.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Membrane Biology and Protein Processing (MBPP)
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Gindhart, Joseph G
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Cornell University
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Urra, Hery; Henriquez, Daniel R; Cánovas, José et al. (2018) IRE1? governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A. Nat Cell Biol 20:942-953
Kim, Geun Hyang; Shi, Guojun; Somlo, Diane Rm et al. (2018) Hypothalamic ER-associated degradation regulates POMC maturation, feeding, and age-associated obesity. J Clin Invest 128:1125-1140
Hwang, Jiwon; Qi, Ling (2018) Quality Control in the Endoplasmic Reticulum: Crosstalk between ERAD and UPR pathways. Trends Biochem Sci 43:593-605
Bhattacharya, Asmita; Sun, Shengyi; Wang, Heting et al. (2018) Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH. EMBO J 37:
Zhu, Shuang; Liu, Hua; Sha, Haibo et al. (2017) PERK and XBP1 differentially regulate CXCL10 and CCL2 production. Exp Eye Res 155:1-14
Qi, Ling; Tsai, Billy; Arvan, Peter (2017) New Insights into the Physiological Role of Endoplasmic Reticulum-Associated Degradation. Trends Cell Biol 27:430-440
Shi, Guojun; Somlo, Diane RM; Kim, Geun Hyang et al. (2017) ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis. J Clin Invest 127:3897-3912
Dijk, Wieneke; Mattijssen, Frits; de la Rosa Rodriguez, Montserrat et al. (2017) Hypoxia-Inducible Lipid Droplet-Associated Is Not a Direct Physiological Regulator of Lipolysis in Adipose Tissue. Endocrinology 158:1231-1251
Oteng, Antwi-Boasiako; Bhattacharya, Asmita; Brodesser, Susanne et al. (2017) Feeding Angptl4-/- mice trans fat promotes foam cell formation in mesenteric lymph nodes without leading to ascites. J Lipid Res 58:1100-1113
Sun, Shengyi; Lourie, Rohan; Cohen, Sara B et al. (2016) Epithelial Sel1L is required for the maintenance of intestinal homeostasis. Mol Biol Cell 27:483-90

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