Vps33B controls Treg cell suppressive function through inhibiting lysosomal nutrient sensing complex-mediated mTORC1 activation

• Published in: Cell reports (Cambridge) 2022-06, Vol.39 (11), p.110943-110943, Article 110943
• Main Authors: Xiang, Hongrui, Tao, Yuexiao, Jiang, Zhenyan, Huang, Xian, Wang, Huizi, Cao, Wei, Li, Jia, Ding, Rui, Shen, Mingyi, Feng, Ru, Li, Linsen, Guan, Chenyang, Liu, Jiamin, Ni, Jun, Chen, Lei, Wang, Zhengting, Ye, Youqiong, Zhong, Qing, Liu, Junling, Zou, Qiang, Wu, Xuefeng
• Format: Article
• Language: English
• Subjects: CP: Immunology; CP: Metabolism; endolysosomal system; Foxp3; mTORC1; Treg; Vps33B
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110943

The suppressive function of regulatory T (Treg) cells is tightly controlled by nutrient-fueled mechanistic target of rapamycin complex 1 (mTORC1) activation, yet its dynamics and negative regulation remain unclear. Here we show that Treg-specific depletion of vacuolar protein sorting 33B (Vps33B) in mice results in defective Treg cell suppressive function and acquisition of effector phenotype, which in turn leads to disturbed T cell homeostasis and boosted antitumor immunity. Mechanistically, Vps33B binds with lysosomal nutrient-sensing complex (LYNUS) and promotes late endosome and lysosome fusion and clearance of the LYNUS-containing late endosome/lysosome, and therefore suppresses mTORC1 activation. Vps33B deficiency in Treg cells results in disordered endosome lysosome fusion, which leads to accumulation of LYNUS that causes elevated mTORC1 activation and hyper-glycolytic metabolism. Taken together, our study reveals that Vps33B maintains Treg cell suppressive function through sustaining endolysosomal homeostasis and therefore restricting amino acid-licensed mTORC1 activation and metabolism. [Display omitted] •Vsp33B is pivotal for restraining lysosomal nutrient-sensing complex accumulation•Vps33B maintains Treg cell function by modulating amino acid-licensed mTORC1 activity•Vps33B modulates Treg cell glycolysis via restricting mTORC1 activation•Late endosome and lysosome fusion is critical for Treg cell suppressive function Xiang et al. show that Vps33B controls regulatory T cell function through modulating mTORC1 activation and metabolism via promoting late endosome lysosome fusion and restricting lysosomal nutrient-sensing complex accumulation.