Yang Shuai, Jin Shouheng, Xian Huifang, Zhao Zhiyao, Wang Liqiu, Wu Yaoxing, Zhou Liang, Li Mengqiu, Cui Jun
Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
Mol Cell. 2023 Jan 19;83(2):298-313.e8. doi: 10.1016/j.molcel.2022.12.007. Epub 2023 Jan 4.
Post-translational modifications (PTMs) of proteins are crucial to guarantee the proper biological functions in immune responses. Although protein phosphorylation has been extensively studied, our current knowledge of protein pyrophosphorylation, which occurs based on phosphorylation, is very limited. Protein pyrophosphorylation is originally considered to be a non-enzymatic process, and its function in immune signaling is unknown. Here, we identify a metabolic enzyme, UDP-N-acetylglucosamine pyrophosphorylase 1 (UAP1), as a pyrophosphorylase for protein serine pyrophosphorylation, by catalyzing the pyrophosphorylation of interferon regulatory factor 3 (IRF3) at serine (Ser) 386 to promote robust type I interferon (IFN) responses. Uap1 deficiency significantly impairs the activation of both DNA- and RNA-viruse-induced type I IFN pathways, and the Uap1-deficient mice are highly susceptible to lethal viral infection. Our findings demonstrate the function of protein pyrophosphorylation in the regulation of antiviral responses and provide insights into the crosstalk between metabolism and innate immunity.
蛋白质的翻译后修饰（PTM）对于确保免疫反应中的正常生物学功能至关重要。尽管蛋白质磷酸化已得到广泛研究，但我们目前对基于磷酸化发生的蛋白质焦磷酸化的了解非常有限。蛋白质焦磷酸化最初被认为是一个非酶促过程，其在免疫信号传导中的功能尚不清楚。在这里，我们鉴定出一种代谢酶，尿苷二磷酸-N-乙酰葡糖胺焦磷酸化酶1（UAP1），作为蛋白质丝氨酸焦磷酸化的焦磷酸化酶，它通过催化干扰素调节因子3（IRF3）丝氨酸（Ser）386位点的焦磷酸化来促进强大的I型干扰素（IFN）反应。Uap1缺陷显著损害DNA病毒和RNA病毒诱导的I型IFN途径的激活，并且Uap1缺陷小鼠对致命病毒感染高度敏感。我们的研究结果证明了蛋白质焦磷酸化在抗病毒反应调节中的功能，并为代谢与先天免疫之间的相互作用提供了见解。
