State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
Development. 2019 Jan 25;146(2):dev169235. doi: 10.1242/dev.169235.
Protein modification by ubiquitin and ubiquitin-like proteins (UBLs) regulates numerous biological functions. The UFM1 system, a novel UBL conjugation system, is implicated in mouse development and hematopoiesis. However, its broad biological functions and working mechanisms remain largely elusive. CDK5RAP3, a possible ufmylation substrate, is essential for epiboly and gastrulation in zebrafish. Herein, we report a crucial role of CDK5RAP3 in liver development and hepatic functions. knockout mice displayed prenatal lethality with severe liver hypoplasia, as characterized by delayed proliferation and compromised differentiation. Hepatocyte-specific knockout mice suffered post-weaning lethality, owing to serious hypoglycemia and impaired lipid metabolism. Depletion of CDK5RAP3 triggered endoplasmic reticulum stress and activated unfolded protein responses in hepatocytes. We detected the interaction of CDK5RAP3 with UFL1, the defined E3 ligase in ufmylation. Notably, loss of CDK5RAP3 altered the ufmylation profile in liver cells, suggesting that CDK5RAP3 serves as a novel substrate adaptor for this UBL modification. Collectively, our study identifies CDK5RAP3 as an important regulator of ufmylation and suggests the involvement of ufmylation in mammalian development.
蛋白质被泛素和泛素样蛋白（UBLs）修饰，调节着众多的生物学功能。UFM1 系统是一种新型的 UBL 连接系统，参与调控小鼠的发育和造血。然而，其广泛的生物学功能和作用机制仍在很大程度上难以捉摸。CDK5RAP3 是 UFM1 系统的一个可能的底物，在斑马鱼的胚层内卷和原肠胚形成中是必需的。在此，我们报告了 CDK5RAP3 在肝脏发育和肝脏功能中的关键作用。CDK5RAP3 基因敲除小鼠在胚胎期发生致死性，肝脏发育严重不全，表现为增殖延迟和分化受损。肝特异性敲除小鼠在断乳后发生致死性，原因是严重的低血糖和脂质代谢受损。CDK5RAP3 的耗竭会引发肝细胞内质网应激和未折叠蛋白反应。我们检测到 CDK5RAP3 与 UFL1 的相互作用，UFL1 是 UFM1 连接酶。值得注意的是，CDK5RAP3 的缺失改变了肝细胞中的 UFM1 修饰谱，表明 CDK5RAP3 是该 UBL 修饰的一种新型底物衔接蛋白。总之，我们的研究确定了 CDK5RAP3 是 UFM1 修饰的一个重要调节剂，并提示了 UFM1 修饰在哺乳动物发育中的参与。
