{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T22:43:57Z","timestamp":1784933037335,"version":"3.55.0"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T00:00:00Z","timestamp":1671667200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T00:00:00Z","timestamp":1671667200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Enteroviral 2A proteinase (2A\n                    <jats:sup>pro<\/jats:sup>\n                    ), a well\u2010established and important viral functional protein, plays a key role in shutting down cellular cap\u2010dependent translation, mainly via its proteolytic activity, and creating optimal conditions for\n                    <jats:italic>Enterovirus<\/jats:italic>\n                    survival. Accumulated data show that viruses take advantage of various signaling cascades for their life cycle; studies performed by us and others have demonstrated that the extracellular signal\u2010regulated kinase (ERK)\u00a0pathway is essential for enterovirus A71 (EV\u2010A71)\u00a0and other viruses replication. We recently showed that ERK1\/2\u00a0is required for the proteolytic activity of viral 2A\n                    <jats:sup>pro<\/jats:sup>\n                    ; however, the mechanism underlying the regulation of 2A\n                    <jats:sup>pro<\/jats:sup>\n                    remains unknown. Here, we demonstrated that the 125th residue Ser125 of EV\u2010A71 2A\n                    <jats:sup>pro<\/jats:sup>\n                    or Thr125 of coxsackievirus B3 2A\n                    <jats:sup>pro<\/jats:sup>\n                    , which is highly conserved in the\n                    <jats:italic>Enterovirus<\/jats:italic>\n                    , was phosphorylated by ERK1\/2. Importantly, 2A\n                    <jats:sup>pro<\/jats:sup>\n                    with phosphor\u2010Ser\/Thr125 had much stronger proteolytic activity toward eukaryotic initiation factor 4GI and rendered the virus more efficient for multiplication and pathogenesis in hSCARB2 knock\u2010in mice than that in nonphospho\u2010Ser\/Thr125A (S\/T125A) mutants. Notably, phosphorylation\u2010mimic mutations caused deleterious changes in 2A\n                    <jats:sup>pro<\/jats:sup>\n                    catalytic function (S\/T125D\/E) and in viral propagation (S125D). Crystal structure simulation analysis showed that Ser125 phosphorylation in EV\u2010A71 2A\n                    <jats:sup>pro<\/jats:sup>\n                    enabled catalytic Cys to adopt an optimal conformation in the catalytic triad His\u2010Asp\u2010Cys, which enhances 2A\n                    <jats:sup>pro<\/jats:sup>\n                    proteolysis. Therefore, we are the first to report Ser\/Thr125 phosphorylation of 2A\n                    <jats:sup>pro<\/jats:sup>\n                    increases enteroviral adaptation to the host to ensure enteroviral multiplication, causing pathogenicity. Additionally, weakened viruses containing a S\/T125A mutation could be a general strategy to develop attenuated\n                    <jats:italic>Enterovirus<\/jats:italic>\n                    vaccines.\n                  <\/jats:p>","DOI":"10.1002\/jmv.28400","type":"journal-article","created":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T04:36:05Z","timestamp":1670906165000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Phosphorylation of enteroviral 2A\n                    <sup>pro<\/sup>\n                    at Ser\/Thr125 benefits its proteolytic activity and viral pathogenesis"],"prefix":"10.1002","volume":"95","author":[{"given":"Yuya","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Microbiology, School of Basic Medical Sciences Peking University Health Science Center Beijing 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