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.