{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:07:02Z","timestamp":1753891622233,"version":"3.41.2"},"reference-count":20,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T00:00:00Z","timestamp":1620691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Enterovirus 71 (EV71) is the major causative pathogen of hand, foot, and mouth disease. The lack of understanding of the virus\u2019s pathogenesis hinders the development of anti-virus drugs and the control of EV71 infection. Our previous studies have demonstrated that both mitochondria and endoplasmic reticulum (ER) were altered significantly in EV71 infected cells, but the mechanism is still unclear. In this study, we investigated the effects of EV71 infection on the expression of INF2, a key regulator factor in ER-Mitochondria communication and mitochondrial fission. We found that INF2 was cleaved in EV71 infected RD cells. The INF2 cleavage occurred at Aspartic 1,051 of INF2 and is mediated by activated caspases, predominantly by activated caspase-2. The subcellular localization of INF2 and caspase-2 was significantly altered in infected cells. We speculate that caspase-2-mediated INF2 cleavage is involved in forming viral replication organelles (ROs) and is a positive feedback regulatory mechanism of mitochondrial disorders caused by EV71 infection.<\/jats:p>","DOI":"10.3389\/fmicb.2021.684953","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T05:09:25Z","timestamp":1620709765000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Enterovirus 71 Induces INF2 Cleavage via Activated Caspase-2 in Infected RD Cells"],"prefix":"10.3389","volume":"12","author":[{"given":"Bei","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chongyang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Congci","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"He","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhendong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1083\/jcb.201709111","article-title":"INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division.","volume":"217","author":"Chakrabarti","year":"2018","journal-title":"J. Cell Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1038\/cmi.2017.44","article-title":"Caspases control antiviral innate immunity.","volume":"14","author":"Chen","year":"2017","journal-title":"Cell Mol. Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1242\/jcs.040691","article-title":"INF2 is an endoplasmic reticulum-associated formin protein.","author":"Chhabra","year":"2009","journal-title":"J. Cell Sci."},{"key":"B4","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1139\/y05-144","article-title":"The ubiquitin-proteasome pathway in viral infections.","volume":"84","author":"Gao","year":"2006","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"B5","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.11553","article-title":"Actin filaments target the oligomeric maturation of the dynamin GTPase Drp1 to mitochondrial fission sites.","volume":"4","author":"Ji","year":"2015","journal-title":"Elife"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006748","article-title":"Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer.","volume":"13","author":"Jin","year":"2017","journal-title":"PLoS Genet."},{"key":"B7","doi-asserted-by":"crossref","first-page":"E2001","DOI":"10.1073\/pnas.1524900113","article-title":"Quantitative MS-based enzymology of caspases reveals distinct protein substrate specificities, hierarchies, and cellular roles.","volume":"113","author":"Julien","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B8","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1126\/science.1228360","article-title":"An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2.","volume":"339","author":"Korobova","year":"2013","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","first-page":"4581","DOI":"10.1007\/s00018-020-03550-7","article-title":"The formin INF2 in disease: progress from 10 years of research.","volume":"77","author":"Labat-de-Hoz","year":"2020","journal-title":"Cell Mol. Life Sci."},{"key":"B10","doi-asserted-by":"crossref","DOI":"10.1038\/cddiscovery.2016.5","article-title":"Caspase-2 resides in the mitochondria and mediates apoptosis directly from the mitochondrial compartment.","volume":"2","author":"Lopez-Cruzan","year":"2016","journal-title":"Cell Death Discov."},{"key":"B11","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.08828","article-title":"A mitochondria-anchored isoform of the actin-nucleating spire protein regulates mitochondrial division.","volume":"4","author":"Manor","year":"2015","journal-title":"Elife"},{"key":"B12","doi-asserted-by":"crossref","first-page":"19.e7","DOI":"10.1016\/j.molcel.2019.02.013","article-title":"Apoptotic Caspases suppress Type I interferon production via the cleavage of cGAS, MAVS, and IRF3.","volume":"74","author":"Ning","year":"2019","journal-title":"Mol. Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"4822","DOI":"10.1091\/mbc.e11-05-0457","article-title":"Splice variant-specific cellular function of the formin INF2 in maintenance of Golgi architecture.","volume":"22","author":"Ramabhadran","year":"2011","journal-title":"Mol. Biol. Cell"},{"key":"B14","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1093\/infdis\/129.3.304","article-title":"An apparently new enterovirus isolated from patients with disease of the central nervous system.","volume":"129","author":"Schmidt","year":"1974","journal-title":"J. Infect. Dis."},{"key":"B15","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1016\/s1473-3099(10)70194-8","article-title":"Virology, epidemiology, pathogenesis, and control of enterovirus 71.","volume":"10","author":"Solomon","year":"2010","journal-title":"Lancet Infect. Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1083\/jcb.201711075","article-title":"ER-mitochondria contacts: actin dynamics at the ER control mitochondrial fission via calcium release.","volume":"217","author":"Steffen","year":"2018","journal-title":"J. Cell Biol."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/cells9051259","article-title":"The role of caspase-2 in regulating cell fate.","volume":"9","author":"Vigneswara","year":"2020","journal-title":"Cells"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003231","article-title":"Enterovirus 71 protease 2Apro targets MAVS to inhibit antiviral type I interferon responses.","volume":"9","author":"Wang","year":"2013","journal-title":"PLoS Pathog."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006674","article-title":"Enterovirus 71 protease 2Apro and 3Cpro differentially inhibit the cellular endoplasmic reticulum-associated degradation (ERAD) pathway via distinct mechanisms, and enterovirus 71 hijacks ERAD component p97 to promote its replication.","volume":"13","author":"Wang","year":"2017","journal-title":"PLoS Pathog."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422x-7-94","article-title":"An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of hand foot and mouth disease in Fuyang city of China.","volume":"7","author":"Zhang","year":"2010","journal-title":"Virol J."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.684953\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T05:09:37Z","timestamp":1620709777000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.684953\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,11]]},"references-count":20,"alternative-id":["10.3389\/fmicb.2021.684953"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2021.684953","relation":{},"ISSN":["1664-302X"],"issn-type":[{"type":"electronic","value":"1664-302X"}],"subject":[],"published":{"date-parts":[[2021,5,11]]},"article-number":"684953"}}