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N6-methyladenosine modification of the subgroup J avian leukosis viral RNAs attenuates host innate immunity via MDA5 signaling

文献类型： 外文期刊

作者： Yu, Mengmeng 1 ; Zhang, Li 1 ; Wang, Ying 1 ; Wang, Suyan 1 ; Liu, Yongzhen 1 ; Liu, Peng 1 ; Chen, Yuntong 1 ; Guo, Ru 1 ; Meng, Lingzhai 1 ; Zhang, Tao 1 ; Fan, Wenrui 1 ; Qi, Xiaole 1 ; Duan, Yulu 1 ; Zhang, Yanping 1 ; Cui, Hongyu 1 ; Gao, Yulong 1 ;

作者机构： 1.Chinese Acad Agr Sci, Avian Immunosuppress Dis Div, State Key Lab Anim Dis Control & Prevent, Harbin Vet Res Inst, Harbin, Peoples R China

2.Yangzhou Univ, Jiangsu Coinnovat Ctr Prevent & Control Important, Yangzhou, Peoples R China

3.Natl Poultry Lab Anim Resource Ctr, Harbin, Peoples R China

期刊名称：PLOS PATHOGENS （ 影响因子：4.9； 五年影响因子：5.4 ）

ISSN： 1553-7366

年卷期： 2025 年 21 卷 4 期

页码：

收录情况： SCI

摘要： Subgroup J avian leukosis virus (ALV-J), a retrovirus, elicits immunosuppression and persistent infections in chickens. Although it is widely acknowledged that ALV-J can evade the host's innate immune defenses, the mechanisms behind this immune evasion remain elusive. N6-methyladenosine (m6A), the most prevalent internal RNA modification, plays a role in innate immune evasion. Our research identified ALV-J as an inefficient stimulator of innate immunity in vitro and in vivo, with its genomic RNA featuring m6A modifications predominantly in the envelope protein (Env) region and 3 ' untranslated region (3 ' UTR). To elucidate the functional consequences of m6A modification, we subsequently generated m6A-deficient ALV-J through its culturing in the DF-1 overexpressing fat mass and obesity-associated protein (FTO) cells. The m6A-deficient ALV-J virus, or its RNAs significantly enhanced IFN-beta production compared to the wild-type (wt) ALV-J, suggesting a pivotal regulatory function of m6A modifications in modulating innate immune response. Mechanistically, the m6A modification of the ALV-J genomic RNA directly impacted its recognition by MDA5, weakening its binding and ubiquitination and attenuating IFN-beta activation. Moreover, m6A-deficient ALV-J, created by inducing mutations in m6A sites within Env and 3 ' UTR, exhibited reduced replication capacity and elevated IFN-beta expression in host cells. Importantly, this phenomenon was abolished in MDA5-knockout DF-1 cells, further demonstrating the core role of MDA5. These data demonstrate that m6A modification of ALV-J genomic RNA dampens the host's innate immune response through MDA5 signaling pathway.

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