IL-7 is a cytokine produced by stromal cells, which binds to IL-7Rα and plays an important role for homeostasis of T lymphocytes. Excessive activities of IL-7-triggered signaling pathways causes autoimmune diseases. How IL-7-triggered signaling and immune effects are regulated is not fully understood. In this study, we show that the membrane-associated RING-CH (MARCH) E3 ligase family member MARCH8 mediates K27-linked polyubiquitination of IL-7Rα, leading to its lysosomal degradation. Site-directed mutagenesis suggests that MARCH8 meditates polyubiquitination of IL-7Rα at K265/K266, and mutation of these residues renders IL-7Rα resistance to MARCH8-mediated polyubiquitination and degradation. MARCH8 deficiency increases IL-7-triggered activation of the downstream transcription factor STAT5 and transcriptional induction of the effector genes in human T lymphoma cells. MARCH8 deficiency also promotes IL-7-triggered T cell proliferation and splenic memory CD8+ T cell differentiation in mice. Our findings suggest that MARCH8 negatively regulates IL-7-triggered signaling by mediating K27-linked polyubiquitination and lysosomal degradation of IL-7Rα, which reveals a negative regulatory mechanism of IL-7-triggered T cell homeostasis.
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http://dx.doi.org/10.4049/jimmunol.2400253 | DOI Listing |
Phytother Res
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Department of Nephrology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, China.
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Center for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Fetscherstraße 74, 01307, Dresden, Germany; University Center of Orthopaedic, Trauma and Plastic Surgery, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Dresden, Germany. Electronic address:
Nat Commun
October 2024
Department of Biochemistry, College of Life Science and Technology, Institute for Bio-medical Convergence Science and Technology, Yonsei University, Seoul, Republic of Korea.
J Immunol
November 2024
Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China; and Research Unit of Innate Immune and Inflammatory Diseases (2019RU063), Chinese Academy of Medical Sciences, Wuhan, China.
IL-7 is a cytokine produced by stromal cells, which binds to IL-7Rα and plays an important role for homeostasis of T lymphocytes. Excessive activities of IL-7-triggered signaling pathways causes autoimmune diseases. How IL-7-triggered signaling and immune effects are regulated is not fully understood.
View Article and Find Full Text PDFOncogene
October 2024
Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Elevated intracellular lipid synthesis is important for hepatocellular carcinoma (HCC) progression. Our study aimed to identify the role of nucleoporin 37 (NUP37) in lipid synthesis and HCC progression. The expression of NUP37 was significantly upregulated in HCC and associated with a poor prognosis.
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