Coirry Carmen, Manessier Julie, Clot Charlène, Mortier Magda, Fauvarque Marie-Odile, Taillebourg Emmanuel
Université Grenoble Alpes, CEA, INSERM, BGE U1038, Grenoble F-38000, France.
Genetics. 2025 Sep 3;231(1). doi: 10.1093/genetics/iyaf131.
Deubiquitinases (DUBs) form a specific class of proteases removing ubiquitin from target proteins. They are involved in the regulation of many cellular processes including cell growth and proliferation. Among them, USP36 is a key regulator of the oncogenic transcription factor c-Myc, preventing its degradation by the proteasome. These 2 proteins form an evolutionary conserved complex providing the opportunity to investigate USP36 mechanisms of action in vivo in a genetically tractable model such as Drosophila melanogaster. Null mutants of dUsp36 die early during larval development and exhibit severe growth defects. Strikingly, we report here that flies expressing a catalytically inactive version of dUSP36 produced by CRISPR/Cas9 gene editing survive to adulthood with only minor growth defects, yet males are infertile. This finding indicates that dUSP36 deubiquitinating activity is dispensable for cell growth but essential for spermatogenesis. Our results thus reveal that dUSP36 functions through both catalytic-dependent and catalytic-independent mechanisms, highlighting a dual mode of action with implications for the understanding of DUBs mechanism of action.
去泛素化酶（DUBs）是一类特殊的蛋白酶，可从靶蛋白上去除泛素。它们参与许多细胞过程的调控，包括细胞生长和增殖。其中，USP36是致癌转录因子c-Myc的关键调节因子，可防止其被蛋白酶体降解。这两种蛋白质形成了一种进化上保守的复合物，为在诸如黑腹果蝇这样的遗传易处理模型中研究USP36在体内的作用机制提供了机会。dUsp36的无效突变体在幼虫发育早期死亡，并表现出严重的生长缺陷。令人惊讶的是，我们在此报告，通过CRISPR/Cas9基因编辑产生的表达催化失活形式的dUSP36的果蝇能够存活至成年期，仅存在轻微的生长缺陷，但雄性不育。这一发现表明，dUSP36的去泛素化活性对于细胞生长并非必需，但对于精子发生至关重要。因此，我们的结果揭示了dUSP36通过催化依赖性和催化非依赖性机制发挥作用，突出了一种双重作用模式，这对于理解DUBs的作用机制具有重要意义。
