SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer

被引：18

作者：

Bhattacharya, Asmita ^{[1
,2
,7
]}

Wei, Juncheng ^{[3
]}

Song, Wenxin ^{[4
]}

Gao, Beixue ^{[3
]}

Tian, Chunyan ^{[5
]}

Wu, Shuangcheng Alivia ^{[1
]}

Wang, Jian ^{[5
]}

Chen, Ligong ^{[4
]}

Fang, Deyu ^{[3
]}

Qi, Ling ^{[1
,6
]}

机构：

[1] Univ Michigan, Dept Mol & Integrat Physiol, Med Sch, Ann Arbor, MI 48105 USA

[2] Cornell Univ, Grad Program Genet Genom & Dev, Ithaca, NY 14853 USA

[3] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA

[4] Tsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Sch Pharmaceut Sci, Beijing 100084, Peoples R China

[5] Beijing Inst Life, Beijing Proteome Res Ctr, Natl Ctr Prot Sci, State Key Lab Prote, Beijing 102206, Peoples R China

[6] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Med Sch, Ann Arbor, MI 48105 USA

[7] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

来源：

ISCIENCE | 2022年 / 25卷 / 10期

关键词：

RETICULUM-ASSOCIATED DEGRADATION; CELL-PROLIFERATION; TUMOR-SUPPRESSOR; CYCLIN D1; WNT5A; EXPRESSION; CARCINOMA; PATHWAY; HOMEOSTASIS; IRE1-ALPHA;

D O I：

10.1016/j.isci.2022.105183

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Endoplasmic reticulum (ER) homeostasis has been implicated in the pathogenesis of various forms of cancer; however, our understanding of the role of 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.

引用

页数：23

共 80 条

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