LZTR1 regulates epithelial MHC-I expression via NF-κB1 to modulate CD8⁺ T cells activation

The role of CD8⁺ tissue-resident memory T (CD8⁺ T_RM) in inflammation is well established. However, the mechanisms by which CD8⁺ T_RM cells are activated in tissues have remained elusive. Here, we show that Leucine zipper-like transcription regulator 1 (LZTR1), a substrate adaptor for cullin3 (CUL3) ubiquitin ligase complex, regulates CD8⁺ T_RM activation and proliferation in cutaneous and colonic epithelia through modulation of major histocompatibility complex class I (MHC-I) expression in an NF-κB1-dependent manner. Mechanistically, LZTR1 modulates MHC-I transcription by regulating co-translational biogenesis of NF-κB1 (p50) in a ubiquitination-independent but proteasome-dependent manner through direct binding with ribosome and proteasome. Loss of LZTR1 leads to suppression of CD8⁺ T_RM activation and proliferation and decreased production of IL-17A with blunting of inflammatory responses in both cutaneous and gut epithelia in vivo. In summary, these data identify LZTR1 as a novel regulator of CD8⁺ T_RM function and provide insights into the mechanisms that drive and maintain CD8⁺ T-cell responses in epithelial-associated autoimmune diseases.