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Chaperone-mediated autophagy is required for regulatory T cell function

ABSTRACT: Chaperone-mediated autophagy (CMA) is a selective form of protein degradation in lysosomes that declines with age. Besides protein quality control, CMA also regulates several cellular processes through timely proteome remodeling. We previously demonstrated the importance of CMA in the activation of helper T cells. In this work, we analyzed the role of CMA in the generation and function of regulatory T cells (Tregs), a specialized type of T cells that suppress immune responses. We found that the basal CMA activity of Tregs further increases upon their activation. Using a Treg-specific CMA-deficient mouse model, we show that CMA is crucial for maintenance of peripheral tolerance by Tregs. Mice with CMA-defective Tregs display signs of chronic inflammation, which results in reduced survival as they age. We demonstrate that CMA-deficient Tregs have reduced suppressive activity in vivo using an experimental model of inflammatory bowel disease and a second model of tumor-induced immune response. Comparative quantitative proteomic analysis enabled us to identify the subproteome degraded by CMA and, consequently, the cellular pathways modulated by this type of autophagy to sustain Treg homeostasis and function. Collectively, our findings uncover a previously unknown role for CMA in regulating Treg function.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Simone Sidoli

LAB HEAD: Simone Sidoli

PROVIDER: PXD072715 | Pride | 2026-04-21

REPOSITORIES: Pride

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			Action	DRS
	250405_Ronnie_Yair_10_4-7-2025_05-13-37_5427.mzML	Mzml
	250405_Ronnie_Yair_11_4-7-2025_06-00-20_5428.mzML	Mzml
	250405_Ronnie_Yair_12_4-7-2025_06-46-57_5429.mzML	Mzml
	250405_Ronnie_Yair_13_4-7-2025_07-33-38_5430.mzML	Mzml
	250405_Ronnie_Yair_14_4-7-2025_08-20-22_5431.mzML	Mzml

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Project description:Human FOXP3+CD25+CD4+ regulatory T cells (Tregs) play a dominant role in the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. We here performed a high-time-resolution dynamic analysis of the transcriptome during the very early phase of human Treg/ CD4+ T-effector cell activation. After constructing a correlation network specific for Tregs based on these dynamic data, we described a strategy to identify key genes by directly analyzing the constructed undirected correlation network. Six out of the top 10 ranked key hubs are known to be important for Treg function or involved in autoimmune diseases. Surprisingly, PLAU (the plasminogen activator urokinase) was among the 4 new key hubs. We here show that PLAU was critical for expression regulation of FOXP3, EOS and several other important Treg genes and the suppressor function of human Tregs. Moreover, we found Plau inhibits murine Treg development and but promotes the suppressive function. Further analysis unveils that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways. Our study shows the potential for identifying novel key genes for complex dynamic biological processes using a network strategy based on high-time-resolution data, and highlights a critical role of PLAU in both human and murine Tregs. The construction of a dynamic correlation network of human Tregs provides a useful resource for the understanding of Treg function and human autoimmune diseases. The high-time-resolution time-series transcriptomic data during the very early phase of human Treg/Teff activation could be generally used for further mechanistic analysis of human Treg function. These data could be further used for biological network analysis, dynamic analysis, modeling by experimental researchers, bioinformaticians, computational biologists and systems biologists. We have measured the genome-wide expression of 38,500 genes (probes) by performing a high-time-resolution time-series analysis during the activation process of human regulatory T cells /CD4+ T-effector cells at 19 time points for the first 6h with an equal interval of 20 min. We have also overexpressed the GARP gene in human effector T cells and measured the genome-scale expression for the GARP-overexpressed cells and ThGFP cells at time point 0, 100 and 360min following activation. The stimulation source used in this work is a combination of anti-CD3/-CD28 Dynal beads with IL2 100U/ml.

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Chaperone-mediated autophagy is required for regulatory T cell function

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