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HRD1‐ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination
Author(s) -
Wei Juncheng,
Chen Lu,
Li Fei,
Yuan Yanzhi,
Wang Yajun,
Xia Wanjun,
Zhang Yuehui,
Xu Yuanming,
Yang Zhao,
Gao Beixue,
Jin Chaozhi,
MeloCardenas Johanna,
Green Richard M,
Pan Hui,
Wang Jian,
He Fuchu,
Zhang Kezhong,
Fang Deyu
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201898942
Subject(s) - endoplasmic reticulum associated protein degradation , biology , ubiquitin ligase , microbiology and biotechnology , endoplasmic reticulum , f box protein , downregulation and upregulation , ubiquitin , protein degradation , unfolded protein response , biochemistry , gene
Abstract The endoplasmic reticulum‐associated protein degradation (ERAD) is responsible for recognizing and retro‐translocating protein substrates, misfolded or not, from the ER for cytosolic proteasomal degradation. HMG‐CoA Reductase (HMGCR) Degradation protein—HRD1—was initially identified as an E3 ligase critical for ERAD. However, its physiological functions remain largely undefined. Herein, we discovered that hepatic HRD1 expression is induced in the postprandial condition upon mouse refeeding. Mice with liver‐specific HRD1 deletion failed to repress FGF21 production in serum and liver even in the refeeding condition and phenocopy the FGF21 gain‐of‐function mice showing growth retardation, female infertility, and diurnal circadian behavior disruption. HRD1‐ERAD facilitates the degradation of the liver‐specific ER‐tethered transcription factor CREBH to downregulate FGF21 expression. HRD1‐ERAD catalyzes polyubiquitin conjugation onto CREBH at lysine 294 for its proteasomal degradation, bridging a multi‐organ crosstalk in regulating growth, circadian behavior, and female fertility through regulating the CREBH‐FGF21 regulatory axis.