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Zhichuan Zhu
First author Zhichuan Zhu PhD, a postdoctoral fellow in Liu lab

STING was identified in 2008 as a critical innate immune sensor to antagonize viral/bacterial infection. Inactivation of STING especially by epigenetic silencing has been shown to facilitate tumor progression. Efforts from various UNC and BCBP labs have recently identified an innate immunity-independent function of STING in kidney cancer that can be explored as a potential therapeutic target in treating kidney cancer. The authors first found that from pan-cancer analyses, STING gene amplification as well as increased expression of STING mRNA and proteins are uniquely observed in kidney cancer patient cohorts. Using in vitro assays and immune-deficient murine models, the authors demonstrated that STING depletion in multiple kidney cancer cells resulted in reduced cell growth and tumor formation, which is independent of immune environment. Further RNA-seq analyses revealed dysregulated cell cycle progression and DNA damage responses upon STING depletion caused cell proliferation defects. By establishing a new STING interactome in kidney cancer by proteomics, the authors found STING interacted with multiple calcium transporters and validated the mitochondrial calcium transporter VDAC2 as a novel STING binding partner and downstream effector in controlling kidney cancer growth. To do so, STING binds VDAC2 to disrupt VDAC2/GRP75 channel formation that is necessary for formation of mitochondria-ER contacts for efficient calcium transfer from ER to mitochondria, thus tunning mitochondrial calcium levels. This is critical for mitochondrial metabolic function and biogenesis that govern kidney cancer growth through modulating mTORC1/S6K pathway activities. The authors further revealed STING palmitoylation at C88/C91 controlled by ZDHHC3/7 is necessary for STING binding with VDAC2 to maintain kidney cancer cell growth. As a result, palmitoylation inhibitors such as 2-BP blocks STING/VDAC2 interactions, leading to inhibition of kidney cancer growth. Interestingly, 2-BP also showed a synergy with FDA-approved sorafenib in reducing kidney tumor formation in animal models. Overall, this study uncovers a new STING function that can be exploited as a potential therapeutic direction in treating kidney cancer.

Link to Publication

Zhu, Z.Zhou, X.Du, H.Cloer, E. W.Zhang, J.Mei, L., Wang, Y.Tan, X.Hepperla, A. J.Simon, J. M.Cook, J. G.Major, M. B.Dotti, G.Liu, P.STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity. Adv. Sci. 2022, 2203718.