[Ubiquitination-mediated regulation of T cell homeostasis and autoimmune diseases]

Ubiquitination is a highly dynamic and reversible post-translational modification that is extensively involved in protein degradation, signal transduction, and functional regulation in eukaryotic cells. Through the coordinated action of the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3) cascade, ubiquitin molecules are conjugated to substrate proteins through distinct ubiquitin chain linkages, thereby determining proteasomal degradation, subcellular trafficking, or non-degradative scaffold functions of target proteins. In the immune system, E3 ligases and deubiquitinases (DUBs) precisely regulate T cell antigen recognition, receptor signaling, activation, proliferation, and effector differentiation by controlling substrate selection and ubiquitin chain editing. By modulating the stability of T cell receptors, co-stimulatory and cytokine signaling molecules, as well as key transcription factors and metabolic regulators, E3 ligases and DUBs influence T cell activation thresholds, anergic states, survival, and differentiation programs. Together, they constitute an essential regulatory network responsible for maintaining T cell homeostasis and peripheral immune tolerance. Dysregulation of this network can enhance pro-inflammatory T cell responses and impaired regulatory T cell function, thereby weakening peripheral immune tolerance and contributing to the development and progression of various autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes mellitus. Systematic summarization of the molecular mechanisms and key signaling pathways through which E3 ligases and DUBs regulate T cell fate, together with elucidation of substrate landscapes, ubiquitin chain preferences, and their metabolic crosstalk among different T cell subsets, will deepen our understanding of how ubiquitination maintains T cell homeostasis and contributes to autoimmune disease pathogenesis. Furthermore, such insights may provide a theoretical foundation and translational directions for the development of chain-specific and cell-type-selective therapeutic strategies.