去泛素酶(DUB)对于维持蛋白质稳态和将蛋白质组装成功能复合物至关重要。尽管人们对DUBs的生物学功能越来越感兴趣,DUB在调节肠干细胞(ISC)和肠道稳态中的作用仍然未知。这里,我们通过诱导敲低成人中肠ISC和肠母细胞(EB)中DUBs的表达进行体内RNAi筛选,以鉴定果蝇中肠道稳态的DUB调节因子。我们筛选了43个DUB,并确定了ISC稳态所需的8个DUB。usp1,CG7857,usp5,rpn8,usp10和csn5的敲除减少了ISC/EB的数量,而CG4968和usp8的敲低增加了ISC/EB的数量。此外,ISC/EBs中usp1,CG4968,CG7857或rpn8的敲低破坏了肠屏障的完整性并缩短了寿命,表明这些DUB对维持肠道稳态的要求。此外,我们提供证据表明Usp1通过调节Notch信号活性介导ISC谱系分化。我们的研究表明,第一次,维持果蝇肠道稳态所需的去泛素酶,并为DUB和肠道稳态之间的功能联系提供新的见解。
Deubiquitinases (DUBs) are essential for the maintenance of protein homeostasis and assembly of proteins into functional complexes. Despite growing interest in DUBs biological functions, the roles of DUBs in regulating intestinal stem cells (ISCs) and gut homeostasis remain largely unknown. Here, we perform an in vivo RNAi screen through induced knock-down of DUBs expression in adult midgut ISCs and enteroblasts (EBs) to identify DUB regulators of intestinal homeostasis in Drosophila. We screen 43 DUBs and identify 8 DUBs that are required for ISCs homeostasis. Knocking-down of usp1, CG7857, usp5, rpn8, usp10 and csn5 decreases the number of ISCs/EBs, while knocking-down of CG4968 and usp8 increases the number of ISCs/EBs. Moreover, knock-down of usp1, CG4968, CG7857, or rpn8 in ISCs/EBs disrupts the intestinal barrier integrity and shortens the lifespan, indicating the requirement of these DUBs for the maintenance of gut homeostasis. Furthermore, we provide evidences that USP1 mediates ISC lineage differentiation via modulating the Notch signaling activity. Our study identifies, for the first time, the deubiquitinases required for the maintenance of intestinal homeostasis in Drosophila, and provide new insights into the functional links between the DUBs and intestinal homeostasis.