SEL1L3 suppresses colorectal cancer cell growth and metastasis by preventing endoplasmic reticulum-associated degradation of STING

  • Cell Death Dis. 2026 May 3;17(1):586. doi: 10.1038/s41419-026-08770-6.
Hui Zhang  1  2  3 ,  Wenli Qian  3  4 ,  Mengying Li  3 ,  Xiuqun Zou  3 ,  Xiaolin Chen  3 ,  Keyan Miao  5 ,  Mai Zhao  6 ,  Mengjiang Xu  3 ,  Jiali Dong  3 ,  Jiamin Wang  3 ,  Haixia Peng  7 ,  Hao Jia  8  9 ,  Zhaoyuan Hou  10  11
Affiliations
  • 1. Digestive Endoscopy Center & SKL-FMR, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 2. Yantai Stomatological Hospital/Peninsula Cancer Research Center, School of Stomatology, Shandong Medical & Pharmaceutical University, Yantai, China.
  • 3. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry & Molecular Cellular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 4. Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 5. Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 6. Trauma Center, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine Shanghai, Shanghai, China.
  • 7. Digestive Endoscopy Center & SKL-FMR, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China. [email protected].
  • 8. Digestive Endoscopy Center & SKL-FMR, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China. [email protected].
  • 9. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry & Molecular Cellular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China. [email protected].
  • 10. Yantai Stomatological Hospital/Peninsula Cancer Research Center, School of Stomatology, Shandong Medical & Pharmaceutical University, Yantai, China. [email protected].
  • 11. Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medical & Pharmaceutical University, Yantai, China. [email protected].
PMID: 42071001 DOI: 10.1038/s41419-026-08770-6
Abstract

Endoplasmic reticulum associated degradation (ERAD) plays pivotal role in protein homeostasis and quality control in normal and Cancer cells, yet the regulatory mechanism of ERAD remains elusive, especially regarding its ubiquitination function mediated by hydroxymethylglutaryl reductase degradation protein 1 (HRD1). Here, we report that Sel-1 Suppressor of Lin-12-Like 3 (SEL1L3) protein resided on the ER membrane can effectively prevent HRD1-mediated ERAD process via dual mechanisms: SEL1L3 disrupts SEL1L-HRD1 complex by mutually exclusively interacting with SEL1L and HRD1 respectively, resulting in concomitant prevention of substrate degradation; on the Other hand, SEL1L3 can accelerate HRD1 protein degradation. Biologically, SEL1L3 inhibits colorectal Cancer (CRC) cell growth and migration, which counteracts the oncogenic activity of HRD1; moreover, we identify STING as a HRD1 substrate and a critical downstream effector mediating tumor suppression activity of SEL1L3. Collectively, these data demonstrate that SEL1L3 is a critical regulator of ERAD and exerts a potent tumor-suppressing function, and that the SEL1L3/HRD1/STING axis plays a crucial role in CRC growth and migration.

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