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2019年度论文动态

CDK5RAP3, a UFL1 substrate adaptor, is crucial for liver development.

Yang R1,2, Wang H1,2, Kang B3, Chen B1,2, Shi Y4, Yang S1,2, Sun L5, Liu Y1,2, Xiao W6, Zhang T6, Yang J1, Zhang Y1,7, Zhu M4, Xu P6, Chang Y1,7, Jia Y8,2, Huang Y8,2


Development. 2019 Jan 25;146(2).

PMID: 30635284


Abstract

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. Cdk5rap3 knockout mice displayed prenatal lethality with severe liver hypoplasia, as characterized by delayed proliferation and compromised differentiation. Hepatocyte-specific Cdk5rap3 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 in vivo 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.


    蛋白分子的泛素和类泛素(UBLs)修饰参与调节许多的生物学功能。UFM1系统是一类新发现的类泛素修饰,它已被证实参与了小鼠的造血发育,但其广泛的生物学功能和作用机制尚待深入研究。我们利用多种基因敲除小鼠模型研究发现:敲除Cdk5rap3基因会导致出生前致死,肝脏严重发育不全。在肝细胞中特异敲除该基因造成动物离乳后死亡,表现出严重的低血糖和受损的脂代谢。Cdk5rap3的缺失在肝细胞中引起内质网应激,激活了UPR;显著改变了Ufm1的底物谱,是这种类泛素修饰的一个底物适配器。本研究首次报道了CDK5RAP3Ufm1系统的一个重要的的调节者,首次揭示了Ufm1系统参与哺乳动物的肝脏发育。相关研究论文发表在发育生物学领域著名学术期刊Development 上。