SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer
Asmita Bhattacharya,
Juncheng Wei,
Wenxin Song,
Beixue Gao,
Chunyan Tian,
Shuangcheng Alivia Wu,
Jian Wang,
Ligong Chen,
Deyu Fang,
Ling Qi
Affiliations
Asmita Bhattacharya
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA; Graduate Program of Genetics, Genomics and Development, Cornell University, Ithaca, NY 14853, USA
Juncheng Wei
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Wenxin Song
School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China
Beixue Gao
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Chunyan Tian
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 102206, China
Shuangcheng Alivia Wu
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
Jian Wang
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 102206, China
Ligong Chen
School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China
Deyu Fang
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Corresponding author
Ling Qi
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA; Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA; Corresponding author
Summary: Endoplasmic reticulum (ER) homeostasis has been implicated in the pathogenesis of various forms of cancer; however, our understanding of the role of ER quality control mechanisms in tumorigenesis remains incomplete. Here, we show that the SEL1L-HRD1 complex of ER-associated degradation (ERAD) suppresses hepatocyte proliferation and tumorigenesis in mice. Hepatocyte-specific deletion of Sel1L or Hrd1 predisposed mice to diet/chemical-induced tumors. Proteomics screen from SEL1L-deficient livers revealed WNT5A, a tumor suppressor, as an ERAD substrate. Indeed, nascent WNT5A was misfolding prone and degraded by SEL1L-HRD1 ERAD in a quality control capacity. In the absence of ERAD, WNT5A misfolds is largely retained in the ER and forms high-molecular weight aggregates, thereby depicting a loss-of-function effect and attenuating WNT5A-mediated suppression of hepatocyte proliferation. In humans, SEL1L-HRD1 ERAD expression correlated positively with survival time for patients with liver cancer. Overall, our data reveal a key role of SEL1L-HRD1 ERAD in suppressing hepatocyte proliferation and liver cancer.
