分层上皮分化涉及转录和蛋白质组重塑。多组分析暗示泛素和相关的翻译后网络在分化动力学。系统扰动原代人角质形成细胞中的泛素样机制，揭示了神经前体细胞表达的发育下调8 （NEDD8）和小泛素相关修饰因子2 （SUMO2）的相反功能。条件敲除小鼠的产生确定了NEDD8在祖细胞维持、皮肤再生和炎症中的重要作用，而SUMO2则是分化所必需的。
除了泛素-蛋白酶体一致性变化外，NEDD8指导的蛋白质组学调节与RNA丰度相关。免疫沉淀-质谱法与全基因组抑制因子筛选的整合揭示了上下文特异性的NEDDylation依赖性。在效应物中，异质核核糖核蛋白U （HNRNPU）是上皮细胞状态的转录后调节剂，其RNA结合库由NEDDylation调节。因此，NEDD8和SUMO2在上皮稳态、再生和炎症中发挥相反的作用，表明泛素样网络以多种方式控制组织稳态。
附：英文原文
Title: Ubiquitin-like proteins NEDD8 and SUMO2 control epithelial homeostasis, regeneration, and inflammation
Author: Mrten C. G. Winge, Leandra V. Jackrazi, Douglas F. Porter, Suhas Srinivasan, Vanessa Lopez-Pajares, Dayan J. Li, Benjamin Pham, Aubrey Houser, Spencer H. Cha, Robin M. Meyers, Lisa A. Ko, Luca Ducoli, Weili Miao, Lindsey M. Meservey, Brian J. Zarnegar, Mark Smith, Andrew L. Ji, Michael T. Longaker, Paul A. Khavari
Issue&Volume: 2026-06-25
Abstract: Stratified epithelial differentiation involves transcriptional and proteomic remodeling. Here, multiomic profiling implicated ubiquitin and related posttranslational networks in differentiation dynamics. Systematic perturbation of ubiquitin-like machinery in primary human keratinocytes which uncovered opposite functions of neural-precursor-cell–expressed, developmentally down-regulated 8 (NEDD8) and small ubiquitin-related modifier 2 (SUMO2). Generation of conditional knockout mice established essential roles for NEDD8 in progenitor maintenance, skin regeneration, and inflammation, whereas SUMO2 was required for differentiation. Beyond ubiquitin-proteasome-concordant changes, NEDD8 directed proteomic regulation correlated with RNA abundance. Integration of immunoprecipitation– mass spectrometry with genome-wide suppressor screening revealed context-specific NEDDylation dependencies. Among effectors, heterogeneous nuclear ribonucleoprotein U (HNRNPU) emerged as a posttranscriptional regulator of epithelial cell state whose RNA binding repertoire was modulated by NEDDylation. Thus, NEDD8 and SUMO2 play opposite roles in epithelial homeostasis, regeneration, and inflammation, demonstrating multiple ways ubiquitin-like networks govern tissue homeostasis.
DOI: aeb3900
Source: https://www.science.org/doi/10.1126/science.aeb3900