2. Academic Validation
  3. STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity

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

  • Adv Sci (Weinh). 2022 Nov 29;e2203718. doi: 10.1002/advs.202203718.
Zhichuan Zhu 1 2,  Xin Zhou 1 3,  Hongwei Du 1 3,  Erica W Cloer 1,  Jiaming Zhang 4,  Liu Mei 2,  Ying Wang 1 2,  Xianming Tan 1 5,  Austin J Hepperla 1 6 7,  Jeremy M Simon 1 6 7 8,  Jeanette Gowen Cook 1 2,  Michael B Major 9,  Gianpietro Dotti 1 3,  Pengda Liu 1 2
Affiliations

Affiliations

  • 1 Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 2 Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 3 Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 4 Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, 02115, USA.
  • 5 Department of Biostatistics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 6 Carolina Institute for Developmental Disabilities, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 7 UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 8 Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 9 Department of Cell Biology and Physiology, Department of Otolaryngology, Washington University in St. Louis, St. Louis, MO, 63130, USA.
PMID: 36445063 DOI: 10.1002/advs.202203718
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.

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