m6A modifications regulate intestinal immunity and rotavirus infection
Anmin Wang, Wanyin Tao, Jiyu Tong, Juanzi Gao, Jinghao Wang, Gaopeng Hou, Chen Qian, Guorong Zhang, Runzhi Li, Decai Wang, Xingxing Ren, Kaiguang Zhang, Siyuan Ding, Richard A Flavell, Huabing Li, Wen Pan, Shu Zhu
Abstract
N6-methyladenosine (m6A) is an abundant mRNA modification that affects many biological processes. Nevertheless, we have a poor understanding of how m6A levels are regulated during physiological or pathological processes such as responses to virus infections. The in vivo function of m6A in intestinal immune defense against virus infections is largely unknown. Here, we describe a novel antiviral function of m6A modification during rotavirus (RV) infection in small bowel intestinal epithelial cells (IECs). We found that rotavirus infection induced global m6A modifications on mRNA transcripts by downregulating the m6a eraser ALKBH5. Mice lacking the m6A writer enzymes METTL3 in IECs ( Mettl3 ΔIEC) were resistant to RV infection and showed increased expression of interferons (IFNs) and IFN-stimulated genes (ISGs). Using RNA-sequencing and m6A RNA immuno-precipitation (RIP)-sequencing, we identified IRF7, a master regulator of IFN responses, as a primary target of m6A during virus infection. In the absence of METTL3, IECs showed increased Irf7 mRNA stability and enhanced type I and III IFN expression. Deficiency in IRF7 attenuated the elevated expression of IFNs and ISGs and restored susceptibility to RV infection in Mettl3 ΔIEC mice. Moreover, the global frequency of m6A modifications on mRNA transcripts declined with age in mice, with a significant drop during the period from 2 weeks to 3 weeks after birth, which is likely to have broad implications for the development of the intestinal immune system against enteric viruses early in life. Collectively, our results demonstrate a novel host m6A-IRF7-IFN antiviral signaling cascade that restricts rotavirus infection in vivo.