@article{235c6852fcc449b5aa3f7330a4ab6c05,
title = "STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity",
abstract = "STING is an innate immune sensor for immune surveillance of viral/bacterial infection and maintenance of an immune-friendly microenvironment to prevent tumorigenesis. However, if and how STING exerts innate immunity-independent function remains elusive. Here, the authors report that STING expression is increased in renal cell carcinoma (RCC) patients and governs tumor growth through non-canonical innate immune signaling involving mitochondrial ROS maintenance and calcium homeostasis. Mitochondrial voltage-dependent anion channel VDAC2 is identified as a new STING binding partner. STING depletion potentiates VDAC2/GRP75-mediated MERC (mitochondria-ER contact) formation to increase mitochondrial ROS/calcium levels, impairs mitochondria function, and suppresses mTORC1/S6K signaling leading to RCC growth retardation. STING interaction with VDAC2 occurs through STING-C88/C91 palmitoylation and inhibiting STING palmitoyl-transferases ZDHHCs by 2-BP significantly impedes RCC cell growth alone or in combination with sorafenib. Together, these studies reveal an innate immunity-independent function of STING in regulating mitochondrial function and growth in RCC, providing a rationale to target the STING/VDAC2 interaction in treating RCC.",
keywords = "2-BP, STING, VDAC2, innate immunity-independent, mTORC1, mitochondrial homeostasis",
author = "Zhichuan Zhu and Xin Zhou and Hongwei Du and Cloer, {Erica W.} and Jiaming Zhang and Liu Mei and Ying Wang and Xianming Tan and Hepperla, {Austin J.} and Simon, {Jeremy M.} and Cook, {Jeanette Gowen} and Major, {Michael B.} and Gianpietro Dotti and Pengda Liu",
note = "Funding Information: The authors thank Liu lab members for critical reading of the manuscript and helpful discussions. The authors sincerely thank colleagues (Drs. Qing Zhang, William Y. Kim, W. Kimryn Rathmell, and others) for kindly sharing various kidney cancer cell lines with us. The authors also thank Travis S. Ptacek for bioinformatics assistance. This work was supported by the Department of Defense Congressionally Directed Medical Research Programs Kidney Cancer Research Program Idea Development Award W81XWH2110419 (PL), Gabrielle's Angel Foundation Medical Research Award (PL), the University of North Carolina at Chapel Hill University Cancer Research Fund (DG, PL), National Institutes of Health grants R01GM102413, R01GM083024 and R35GM141833 (JGC), Department of Defense Congressionally Directed Medical Research Programs Kidney Cancer Research Program Concept Award W81XWH‐18‐1‐0441 (HD), Vicky Amidon Innovation Award in Lung Cancer Research from the Lung Cancer Initiative of North Carolina (HD). Electron Microscopy was performed at the UNC Hooker Imaging Core Facility. The UNC Hooker Imaging Core and the UNC Flow Cytometry Core Facility were supported in part by a National Institutes of Health Cancer Core Support Grant to the UNC Lineberger Comprehensive Cancer Center (CA016086). Publisher Copyright: {\textcopyright} 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.",
year = "2023",
month = jan,
day = "25",
doi = "10.1002/advs.202203718",
language = "English",
volume = "10",
journal = "Advanced Science",
issn = "2198-3844",
number = "3",
}