Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells

• 成果类型: Article
• 署名作者: Wang, Jing; Ni, Zegui; Zhang, Xinxin; He, Linling; Zhang, Xinyue; Cheng, Xu; Wang, Haimo; Sun, Guoying; Lu, Zhenwei; Liu, Chengxu; Qian, Hongjie; Lu, Youli; Liu, Gangyi; Jia, Jingying; Ye, Jian; Huang, Linzhang; Ye, Haobin; Li, Rong; Tao, Wufan; Li, Peng; Zhao, Tong-Jin; Du, Xingrong
• 署名单位: Fudan University; City of Hope; Fudan University; Fudan University; Fudan University; Shanghai Qi Zhi Institute; Zhengzhou University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2601318123
• 发表日期: 2026-09-01
• 页码: e2601318123
• 关键词: CORVET/HOPS; T cells; amino acid; integrated stress response; metabolism; naive; quiescence; transport; immunity; cancer

摘要

Amino acid sufficiency is critical for T cell metabolic reprogramming, yet how T cells maintain amino acid homeostasis remains poorly defined. Here, we identify the CORVET and HOPS (CORVET/HOPS) tethering complexes as essential upstream regulators. In activated T cells, they sustain intracellular amino acid levels by promoting macropinocytosis to acquire extracellular nutrients. This function enables dual signaling outcomes: suppression of the integrated stress response (ISR) and activation of mTORC1, which together license metabolic plasticity and effector function. Genetic ablation of core subunits (VPS18 or VPS11) of CORVET/HOPS induces severe amino acid scarcity, triggers pathological ISR activation, and impairs mTORC1 signaling, leading to reduced peripheral T cell numbers and abrogating both inflammatory and protective immunity in vivo. These defects are mechanistically linked: BIM deletion or enforced mTORC1 activity rescues the survival and proliferative failures, respectively, of CORVET/HOPS-deficient T cells. Our work establishes CORVET/HOPS as fundamental couplers linking nutrient acquisition to immune signaling, revealing a targetable node for immuno-metabolic therapy.