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2019年度論文動態

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.


    蛋白分子的泛素和類泛素(UBLs)修飾參與調節許多的生物學功能。UFM1系統是一類新發現的類泛素修飾,它已被證實參與了小鼠的造血發育,但其廣泛的生物學功能和作用機制尚待深入研究。我們利用多種基因敲除小鼠模型研究發現:敲除Cdk5rap3基因會導致出生前致死,肝髒嚴重發育不全。在肝細胞中特異敲除該基因造成動物離乳後死亡,表現出嚴重的低血糖和受損的脂代謝。Cdk5rap3的缺失在肝細胞中引起內質網應激,激活了UPR;顯著改變了Ufm1的底物譜,是這種類泛素修飾的一個底物適配器。本研究首次報道了CDK5RAP3Ufm1系統的一個重要的的調節者,首次揭示了Ufm1系統參與哺乳動物的肝髒發育。相關研究論文發表在發育生物學領域著名學術期刊Development 上。