甲型流感病毒感染激活信号转导和转录激活因子3（STAT3），以增强固醇调节元件结合蛋白2（SREBP2）的表达、胆固醇生物合成及病毒复制。

Influenza A virus infection activates STAT3 to enhance SREBP2 expression, cholesterol biosynthesis, and virus replication.

作者信息

Zhang Jingting, Wu Yunhan, Wang Yujie, Liu Penggang, Liu Kaituo, Sun Jing, Zhang Pinghu, Wang Xiaoquan, Liu Xiufan, Xu Xiulong

机构信息

College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, China.

Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou 225009, Jiangsu Province, China.

出版信息

iScience. 2024 Jun 29;27(8):110424. doi: 10.1016/j.isci.2024.110424. eCollection 2024 Aug 16.

DOI:10.1016/j.isci.2024.110424

PMID:39108727

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11301072/

Abstract

Cellular cholesterol plays an important role in influenza A virus (IAV) endocytosis and replication. However, how IAV infection regulates cholesterol biosynthesis remains poorly understood. Here, we report that IAV infection activates SREBP2 and induces the expression of HMGCR, a rate-limiting enzyme in cholesterol synthesis pathway. SREBP2 deficiency suppresses IAV-induced HMGCR expression and virus replication. Mechanistically, IAV infection activates JAK2 and STAT3, inhibition of JAK2 and STAT3 activity by their inhibitors or by gene knockout downregulates IAV-induced SREBP2 and HMGCR expression and IAV replication, reduces the content of cellular cholesterol and virus binding to host cells. Exogenous cholesterol reverses the inhibitory effect of S3I-201 and STAT3 deficiency on virus replication. STAT3 or JAK2 overexpression increases the expression of SREBP2 and its downstream target genes, leading to increased IAV replication. These observations collectively suggest that STAT3 activation facilitates IAV replication by inducing SREBP2 expression and increasing cholesterol biosynthesis.

摘要

细胞胆固醇在甲型流感病毒（IAV）的内吞作用和复制中起着重要作用。然而，IAV感染如何调节胆固醇生物合成仍知之甚少。在此，我们报告IAV感染激活SREBP2并诱导HMGCR的表达，HMGCR是胆固醇合成途径中的限速酶。SREBP2缺陷抑制IAV诱导的HMGCR表达和病毒复制。机制上，IAV感染激活JAK2和STAT3，用其抑制剂或通过基因敲除抑制JAK2和STAT3活性会下调IAV诱导的SREBP2和HMGCR表达以及IAV复制，降低细胞胆固醇含量和病毒与宿主细胞的结合。外源性胆固醇可逆转S3I-201和STAT3缺陷对病毒复制的抑制作用。STAT3或JAK2过表达增加SREBP2及其下游靶基因的表达，导致IAV复制增加。这些观察结果共同表明，STAT3激活通过诱导SREBP2表达和增加胆固醇生物合成促进IAV复制。