BAG2 inhibits the proliferation and migration of cervical cancer by slowing the degradation of STING

The fourth most prevalent illness in the world among women, cervical cancer has significant negative effects on both health and the economy in addition to high rates of morbidity and death. Understanding its molecular basis to guide clinical management is critical. STING, an innate immune sensor that induces type I interferon, plays a key role in enhancing anti-tumor activity. Despite the growing interest in the role played by STING in cervical cancer, the homeostatic regulatory mechanisms of STING in cervical cancer remain unknown. Here, we found that the BAG2-STUB1 complex regulates ubiquitin proteasomal degradation of STING, which affects the development of cervical cancer. Mechanistically, BAG2 inhibits ubiquitination of STING and stabilizes it by interacting with STING. Specifically, BAG2 inhibits STUB1 from linking the K48-conjugated ubiquitin chains at K338 and K370 of STING by forming a complex with STUB1. Functionally, upregulation of BAG2 expression could inhibit cervical cancer progression by activating the type I interferon response in a STING-dependent manner. Importantly, clinical cervical cancer samples showed a positive correlation between BAG2 and STING expression, and low BAG2 expression was strongly associated with clinical progression and poor prognosis in cervical cancer. Together, these findings describe the molecular mechanism by which the BAG2-STUB1 complex mediates the homeostatic regulation of STING, highlighting the important potential role of BAG2 in the diagnosis and treatment of cervical cancer.