HRD1-ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination

Juncheng Wei, Lu Chen, Fei Li, Yanzhi Yuan, Yajun Wang, Wanjun Xia, Yuehui Zhang, Yuanming Xu, Zhao Yang, Beixue Gao, Chaozhi Jin, Johanna Melo-Cardenas, Richard M. Green, Hui Pan*, Jian Wang, Fuchu He, Kezhong Zhang, Deyu Fang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish (US)
Article numbere98942
JournalEMBO Journal
Issue number22
StatePublished - Nov 15 2018


  • ER-associated degradation
  • FGF21
  • HRD1
  • multi-organ crosstalk

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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