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(lèi)泛素（UBLs）修飾參與調節許多的生物學(xué)功能。UFM1系統是一類(lèi)新發(fā)現的類(lèi)泛素修飾，它已被證實(shí)參與了小鼠的造血發(fā)育，但其廣泛的生物學(xué)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(fā)現：敲除Cdk5rap3基因會(huì )導致出生前致死，肝臟嚴重發(fā)育不全。在肝細胞中特異敲除該基因造成動(dòng)物離乳后死亡，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(zhì)網(wǎng)應激，激活了UPR；顯著(zhù)改變了Ufm1的底物譜，是這種類(lèi)泛素修飾的一個(gè)底物適配器。本研究首次報道了CDK5RAP3是Ufm1系統的一個(gè)重要的的調節者，首次揭示了Ufm1系統參與哺乳動(dòng)物的肝臟發(fā)育。相關(guān)研究論文發(fā)表在發(fā)育生物學(xué)領(lǐng)域著(zhù)名學(xué)術(shù)期刊Development 上。