Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells
- Jing Wang
- Zegui Ni
- Xinxin Zhang
- Linling He
- Xinyue Zhang
- Xu Cheng
- Haimo Wang
- Guoying Sun
- Zhenwei Lu
- Chengxu Liu
- Hongjie Qian
- Youli Lu
- Gangyi Liu
- Jingying Jia
- Jian Ye
- Linzhang Huang
- Haobin Ye
- Rong Li
- Wufan Tao
- Peng Li
- Tong-Jin Zhao
- Xingrong Du
2026-08-26
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.