ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

Shi, Guojun; Somlo, Diane R.M.; Kim, Geun Hyang; Prescianotto-Baschong, Cristina; Sun, Shengyi; Beuret, Nicole; Long, Qiaoming; Rutishauser, Jonas; Arvan, Peter; Spiess, Martin; Qi, Ling

doi:10.1172/jci94771

Cited by 69 publications

(83 citation statements)

References 57 publications

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“…Our data show that the effect of ER stress on Crebh and Fgf21 expression pales when compared to that of Sel1L‐Hrd1 ERAD deficiency in the liver or hepatocytes. Moreover, our data showed that Sel1L deficiency only triggers very moderate ER stress response, likely due to cellular adaptation as shown in other cell types (Kim et al , ; Shi et al , ). Hence, while modest but tonic ER stress may contribute somewhat to the overall phenotype of the Sel1L‐deficient mice, the marked elevation of Fgf21 is likely a direct result of Crebh stabilization and accumulation in the absence of Sel1L‐Hrd1 ERAD.…”

Section: Discussionsupporting

confidence: 78%

“…Subsequent characterization of cell type‐specific Sel1L‐knockout (Ji et al , ; Sha et al , ; Shi et al , ; Sun et al , , , ) and Hrd1‐knockout (Fujita et al , ; Kong et al , ; Wu et al , ; Xu et al , ; Yang et al , ) mouse models, including gene deletion in adipocytes, immune cells, enterocytes, and various neurons, has revealed the significance of Sel1L‐Hrd1 ERAD in a cell type‐ and substrate‐specific manner in vivo (Qi et al , ). For example, mice with Sel1L deficiency in adipocytes exhibit lipodystrophy and postprandial hyperlipidemia due to the ER retention of lipoprotein lipase (LPL) (Sha et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Hepatic Sel1L‐Hrd1 ER‐associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH

et al. 2018

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Fibroblast growth factor 21 (Fgf21) is a liver‐derived, fasting‐induced hormone with broad effects on growth, nutrient metabolism, and insulin sensitivity. Here, we report the discovery of a novel mechanism regulating Fgf21 expression under growth and fasting‐feeding. The Sel1L‐Hrd1 complex is the most conserved branch of mammalian endoplasmic reticulum (ER)‐associated degradation (ERAD) machinery. Mice with liver‐specific deletion of Sel1L exhibit growth retardation with markedly elevated circulating Fgf21, reaching levels close to those in Fgf21 transgenic mice or pharmacological models. Mechanistically, we show that the Sel1L‐Hrd1 ERAD complex controls Fgf21 transcription by regulating the ubiquitination and turnover (and thus nuclear abundance) of ER‐resident transcription factor Crebh, while having no effect on the other well‐known Fgf21 transcription factor Pparα. Our data reveal a physiologically regulated, inverse correlation between Sel1L‐Hrd1 ERAD and Crebh‐Fgf21 levels under fasting‐feeding and growth. This study not only establishes the importance of Sel1L‐Hrd1 ERAD in the liver in the regulation of systemic energy metabolism, but also reveals a novel hepatic “ERAD‐Crebh‐Fgf21” axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Hepatic Sel1L‐Hrd1 ER‐associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH

et al. 2018

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“…Additionally, GRP78 mRNA is reportedly expressed in neurons in the hypothalamic PVN that produce arginine vasopressin (AVP), an antidiuretic hormone, which is also involved in energy homeostasis 36 . Interestingly, PVN AVP neurons are known to interact with the melanocortin system to regulate feeding behavior 37 , and more recently, the colocalization of AVP and GRP78 has been associated with the regulation of ER-associated degradation of AVP in the hypothalamus 38 . These lines of evidence led to the hypothesis that the ability of GRP78 to target specific proteins in specific neuronal populations is responsible for protein trafficking and/or clearing in the brain and may be associated with diverse physiological processes.…”

Section: Discussionmentioning

confidence: 99%

Glucose-regulated protein 78 binds to and regulates the melanocortin-4 receptor

et al. 2018

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The melanocortin-4 receptor (MC4R) belongs to the G protein-coupled receptor (GPCR) family and plays an essential role in the control of energy homeostasis. Here, we identified a novel MC4R-interacting protein, glucose-regulated protein 78 (GRP78), from a pulldown assay using hypothalamic protein extracts and the third intracellular loop of MC4R. We found that MC4R interacted with GRP78 in both the cytosol and at the cell surface and that this interaction increased when MC4R was internalized in the presence of the agonist melanotan-II (MTII). Downregulation of GRP78 using a short interfering RNA approach attenuated MTII-mediated receptor internalization. Reduction in GRP78 expression during tunicamycin-induced endoplasmic reticulum stress also suppressed MTII-mediated internalization of MC4R and cAMP-mediated transcriptional activity. Furthermore, lentiviral-mediated short hairpin RNA knockdown of endogenous GRP78 in the paraventricular nucleus (PVN) of the hypothalamus resulted in an increase in body weight in mice fed a high-fat diet. These results suggest that GRP78 in the PVN binds to MC4R and may have a chaperone-like role in the regulation of MC4R trafficking and signaling.

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“…The Sel1L-Hrd1 protein complex represents the most evolutionarily conserved ERAD machinery (15), in which the single-span ER-transmembrane protein Sel1L is an obligatory cofactor for the ER-resident E3 ligase Hrd1 (16)(17)(18)(19). Using cell type-specific animal models, recent studies from several groups, including ours, have shown that mammalian Sel1L-Hrd1 ERAD mediates indispensable homeostatic processes, such as immune cell development, systemic water balance, food intake, and energy metabolism, in a largely substrate-specific manner (20)(21)(22)(23)(24)(25)(26)(27)(28). However, the physiological significance of ERAD in β cells has remained largely unclear.…”

Section: Introductionmentioning

confidence: 98%

Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling

Shrestha

Liu

et al. 2020

Journal of Clinical Investigation

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ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

Cited by 69 publications

References 57 publications

Hepatic Sel1L‐Hrd1 ER‐associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH

Hepatic Sel1L‐Hrd1 ER‐associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH

Glucose-regulated protein 78 binds to and regulates the melanocortin-4 receptor

Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling

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