Rappaport Research Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Division of Pediatric Hematology and Oncology, Washington University, Saint-Louis, United States.
Elife. 2021 Feb 25;10:e62312. doi: 10.7554/eLife.62312.
A hallmark of aging is loss of differentiated cell identity. Aged midgut differentiated enterocytes (ECs) lose their identity, impairing tissue homeostasis. To discover identity regulators, we performed an RNAi screen targeting ubiquitin-related genes in ECs. Seventeen genes were identified, including the deubiquitinase Non-stop (CG4166). Lineage tracing established that acute loss of Non-stop in young ECs phenocopies aged ECs at cellular and tissue levels. Proteomic analysis unveiled that Non-stop maintains identity as part of a Non-stop identity complex (NIC) containing E(y)2, Sgf11, Cp190, (Mod) mdg4, and Nup98. Non-stop ensured chromatin accessibility, maintaining the EC-gene signature, and protected NIC subunit stability. Upon aging, the levels of Non-stop and NIC subunits declined, distorting the unique organization of the EC nucleus. Maintaining youthful levels of Non-stop in wildtype aged ECs safeguards NIC subunits, nuclear organization, and suppressed aging phenotypes. Thus, Non-stop and NIC, supervise EC identity and protects from premature aging.
衰老的一个标志是分化细胞身份的丧失。衰老的中肠分化肠上皮细胞 (EC) 失去其身份，损害组织稳态。为了发现身份调节剂，我们在 EC 中针对泛素相关基因进行了 RNAi 筛选。鉴定出了 17 个基因，包括去泛素化酶 Non-stop (CG4166)。谱系追踪表明，年轻 EC 中 Non-stop 的急性缺失在细胞和组织水平上模拟了衰老的 EC。蛋白质组学分析表明，Non-stop 作为 Non-stop 身份复合物 (NIC) 的一部分维持身份，该复合物包含 E(y)2、Sgf11、Cp190、(Mod)mdg4 和 Nup98。Non-stop 确保染色质可及性，维持 EC 基因特征，并保护 NIC 亚基稳定性。随着衰老，Non-stop 和 NIC 亚基的水平下降，破坏了 EC 核的独特组织。在野生型衰老 EC 中保持年轻的 Non-stop 水平可保护 NIC 亚基、核组织和抑制衰老表型。因此，Non-stop 和 NIC 监督 EC 身份并防止过早衰老。
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