STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity

• DOI: 10.1002/advs.202203718
• Publication Date: 2022-11-29T13:37:03Z
• Authors: Zhichuan Zhu; Xin Zhou; Hongwei Du; Erica W. Cloer; Jiaming Zhang; Liu Mei; Ying Wang; Xianming Tan; Austin J. Hepperla; Jeremy M. Simon; Jeanette Gowen Cook; Michael B. Major; Gianpietro Dotti; Pengda Liu
• Keywords: Sting; Mitochondrial ROS; ULK1

Abstract STING is an innate immune sensor for surveillance of viral/bacterial infection and maintenance immune‐friendly microenvironment to prevent tumorigenesis. However, if how exerts immunity‐independent function remains elusive. Here, the authors report that expression increased in renal cell carcinoma (RCC) patients governs tumor growth through non‐canonical signaling involving mitochondrial ROS calcium homeostasis. Mitochondrial voltage‐dependent anion channel VDAC2 identified as a new binding partner. depletion potentiates VDAC2/GRP75‐mediated MERC (mitochondria‐ER contact) formation increase ROS/calcium levels, impairs mitochondria function, suppresses mTORC1/S6K leading RCC retardation. interaction with occurs STING‐C88/C91 palmitoylation inhibiting palmitoyl‐transferases ZDHHCs by 2‐BP significantly impedes alone or combination sorafenib. Together, these studies reveal regulating RCC, providing rationale target STING/VDAC2 treating RCC.