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

  • Cell Rep. 2022 Jun 14;39(11):110943. doi: 10.1016/j.celrep.2022.110943.
Hongrui Xiang  1 ,  Yuexiao Tao  1 ,  Zhenyan Jiang  1 ,  Xian Huang  1 ,  Huizi Wang  1 ,  Wei Cao  1 ,  Jia Li  1 ,  Rui Ding  2 ,  Mingyi Shen  3 ,  Ru Feng  3 ,  Linsen Li  4 ,  Chenyang Guan  1 ,  Jiamin Liu  1 ,  Jun Ni  1 ,  Lei Chen  3 ,  Zhengting Wang  5 ,  Youqiong Ye  3 ,  Qing Zhong  4 ,  Junling Liu  6 ,  Qiang Zou  7 ,  Xuefeng Wu  8
Affiliations
  • 1. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4. Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 5. Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6. Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
  • 7. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
  • 8. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
PMID: 35705052 DOI: 10.1016/j.celrep.2022.110943
Abstract

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.

Keywords
CP: Immunology; CP: Metabolism; Foxp3; Treg; Vps33B; endolysosomal system; mTORC1.
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