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

作者：Rundong Jiang, Zhiqin Fang, Yutong Wang, Bo Huang, Junkun Liu, Lam C. Tsoi, Rachael Bogle, Z. Zhang, Yehong Kuang, Xin Zhiguo Li, Dong Liang, Liping Jin, Jóhann E. Guðjónsson, Mingzhu Yin, Xiang Chen · 发表于：Cell Discovery · 年份：2025 · DOI：10.1038/s41421-025-00837-6 · 被引用次数：2 · 研究领域：T-cell and B-cell Immunology、NF-κB Signaling Pathways、Psoriasis: Treatment and Pathogenesis

Abstract 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.