Hepatic SEL1L-HRD1 ER-associated degradation regulates systemic iron homeostasis via ceruloplasmin

Pattaraporn Thepsuwan, Asmita Bhattacharya, Zhenfeng Song, Stephen Hippleheuser, Shaobin Feng, Xiaoqiong Wei, Nupur K. Das, Mariana Sierra, Juncheng Wei, Deyu Fang, Yu Ming M. Huang, Kezhong Zhang, Yatrik M. Shah, Shengyi Sun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Iron homeostasis is critical for cellular and organismal function and is tightly regulated to prevent toxicity or anemia due to iron excess or deficiency, respectively. However, subcellular regulatory mechanisms of iron remain largely unexplored. Here, we report that SEL1L-HRD1 protein complex of endoplasmic reticulum (ER)-associated degradation (ERAD) in hepatocytes controls systemic iron homeostasis in a ceruloplasmin (CP)-dependent, and ER stress-independent, manner. Mice with hepatocyte-specific Sel1L deficiency exhibit altered basal iron homeostasis and are sensitized to iron deficiency while resistant to iron overload. Proteomics screening for a factor linking ERAD deficiency to altered iron homeostasis identifies CP, a key ferroxidase involved in systemic iron distribution by catalyzing iron oxidation and efflux from tissues. Indeed, CP is highly unstable and a bona fide substrate of SEL1L-HRD1 ERAD. In the absence of ERAD, CP protein accumulates in the ER and is shunted to refolding, leading to elevated secretion. Providing clinical relevance of these findings, SEL1L-HRD1 ERAD is responsible for the degradation of a subset of disease-causing CP mutants, thereby attenuating their pathogenicity. Together, this study uncovers the role of SEL1L-HRD1 ERAD in systemic iron homeostasis and provides insights into protein misfolding-associated proteotoxicity.

Original languageEnglish (US)
Article numbere2212644120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number2
StatePublished - Jan 10 2023


  • ceruloplasmin
  • hepatocytes
  • iron metabolism

ASJC Scopus subject areas

  • General


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