STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity.
STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity.
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DOI：
10.1002/advs.202203718
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发表时间：
2023-01
期刊：
影响因子：
15.1
通讯作者：
Liu, Pengda
中科院分区：
文献类型：
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作者：
Zhu, Zhichuan;Zhou, Xin;Du, Hongwei;Cloer, Erica W.;Zhang, Jiaming;Mei, Liu;Wang, Ying;Tan, Xianming;Hepperla, Austin J.;Simon, Jeremy M.;Cook, Jeanette Gowen;Major, Michael B.;Dotti, Gianpietro;Liu, Pengda
SING是一种天然免疫传感器，用于对病毒/细菌感染进行免疫监测，并维持有利于免疫的微环境以防止肿瘤发生。然而，STING是否以及如何发挥先天免疫非依赖功能仍然难以捉摸。在这里，作者报告了肾细胞癌(RCC)患者中STING表达增加，并通过涉及线粒体ROS维持和钙稳态的非规范先天免疫信号来调控肿瘤生长。线粒体电压依赖性阴离子通道VDAC2是一种新的刺激性结合伙伴。STING缺失增强VDAC2/GRP75介导的线粒体-内质网接触蛋白(MERC)的形成，增加线粒体ROS/钙水平，损害线粒体功能，抑制mTORC1/S6K信号转导，导致肾细胞癌生长迟缓。STING与VDAC2的相互作用是通过STING-C88/C91棕榈酰化实现的，2-BP抑制STING棕榈酰转移酶ZDHHCs可显著抑制肾癌细胞的生长或与索拉非尼联合应用。综上所述，这些研究揭示了STING在调节肾细胞癌线粒体功能和生长方面的先天免疫依赖性功能，为靶向STING/VDAC2相互作用治疗RCC提供了理论基础。刺痛是一种典型的先天免疫传感器，可触发I型干扰素的产生。本文报道了通过结合线粒体钙转运蛋白VDAC2来调节线粒体钙稳态来调控肾癌细胞(RCC)增殖的先天免疫非依赖性的刺痛功能，以及它在治疗RCC中的潜在治疗作用。
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. STING is a canonical innate immune sensor triggering type‐I interferon production. Here, an innate immunity‐independent STING function in governing renal cancer cell (RCC) proliferation is reported through regulating mitochondria calcium homeostasis by binding mitochondrial calcium transporter VDAC2, as well as its therapeutic potential in treating RCC.
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DOI：
10.1073/pnas.1512832112
发表时间：
2015-12-15
影响因子：
11.1
作者：
Demaria, Olivier;De Gassart, Aude;Gilliet, Michel
通讯作者：
Gilliet, Michel
DOI：
10.1038/s41577-021-00524-z
发表时间：
2021-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Decout A;Katz JD;Venkatraman S;Ablasser A
通讯作者：
Ablasser A
内膜的四十千克蛋白是线粒体钙Uniporter。
影响因子：
64.8
作者：
De Stefani, Diego;Raffaello, Anna;Teardo, Enrico;Szabo, Ildiko;Rizzuto, Rosario
通讯作者：
Rizzuto, Rosario
钙和ROS：相互互动。
影响因子：
11.4
作者：
Görlach A;Bertram K;Hudecova S;Krizanova O
通讯作者：
Krizanova O
影响因子：
64.8
作者：
通讯作者：
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