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It can infect both pediatric and adult populations, often leading to atypical HFMD. The host innate immune system plays a vital role in the development of enteroviral infections. However, the interplay between the host antiviral response and CV-A6 has not been well investigated. In the present study, we demonstrated that the 2C protein from CV-A6 (2C\n            <jats:sub>CV-A6<\/jats:sub>\n            ) suppresses interferon beta (IFN-\u03b2) production in HEK293T cells. Further results indicated that 2C\n            <jats:sub>CV-A6<\/jats:sub>\n            interacts with both melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I) and induces the degradation of these RNA sensors through proteases in the lysosomal pathway. This function also applies to 2C proteins from enterovirus A71 (2C\n            <jats:sub>EV-A71<\/jats:sub>\n            ) and coxsackievirus B3 (2C\n            <jats:sub>CV-B3<\/jats:sub>\n            ) but not CV-A16 2C (2C\n            <jats:sub>CV-A16<\/jats:sub>\n            ) for its incompetence in MDA5 and RIG-I recognition. Partial depletion and amino acid substitution analyses indicated that the F28A, V75A, and I96V mutations significantly compromised 2C\n            <jats:sub>CV-A6<\/jats:sub>\n            -induced MDA5\/RIG-I depletion. Surprisingly, unlike V75A and I96V that interrupt the 2C\n            <jats:sub>CV-A6<\/jats:sub>\n            -MDA5\/RIG-I interaction, 2C\n            <jats:sub>CV-A6<\/jats:sub>\n            F28A remained competent in MDA5\/RIG-I binding, suggesting that the interaction alone is not sufficient for 2C-mediated reduction. Additional tests indicated that CV-A6 viruses containing the 2C F28A mutation were less efficient in IFN-\u03b2 suppression, which is associated with compromised viral replication and release in infected rhabdomyosarcoma (RD) cells, suggesting that 2C-mediated immune regulation plays a vital role in enteroviral replication. Taken together, our data reveal a novel mechanism by which enteroviral 2C proteins antagonize the host innate antiviral immune response.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Coxsackievirus A6 (CV-A6) is a major emerging pathogen associated with atypical hand, foot, and mouth disease and can cause serious complications such as encephalitis, acute flaccid paralysis, and neurorespiratory syndrome. Therefore, revealing the associated pathogenic mechanisms could benefit the control of CV-A6 infections. In this study, we demonstrate that the nonstructural 2C\n              <jats:sub>CV-A6<\/jats:sub>\n              suppresses IFN-\u03b2 production, which supports CV-A6 infection. This is achieved by depleting RNA sensors such as melanoma differentiation-associated gene 5 and retinoic acid-inducible gene I (RIG-I) through the lysosomal pathway. Such a function is shared by 2C\n              <jats:sub>EV-A71<\/jats:sub>\n              and 2C\n              <jats:sub>CV-B3<\/jats:sub>\n              but not 2C\n              <jats:sub>CV-A16<\/jats:sub>\n              , suggesting the latter might have an alternative way to promote viral replication. This study broadens our understanding of enterovirus 2C protein regulation of the RIG-I-like receptor signaling pathway and reveals a novel mechanism by which CV-A6 and other enteroviruses evade the host innate immune response. These findings on 2C may provide new therapeutic targets for the development of effective inhibitors against CV-A6 and other enterovirus infections.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.01075-23","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T16:26:04Z","timestamp":1697559964000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["Coxsackievirus A6 2C protein antagonizes IFN-\u03b2 production through MDA5 and RIG-I depletion"],"prefix":"10.1128","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6847-4494","authenticated-orcid":false,"given":"Shao-Hua","family":"Wang","sequence":"first","affiliation":[{"name":"Center of Infectious Diseases and Pathogen Biology, First Hospital of Jilin University , Changchun, China"},{"name":"Institute of Virology and AIDS Research, First Hospital of Jilin University , Changchun, 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