{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:46:04Z","timestamp":1784767564145,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1009066","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,24]],"date-time":"2021-02-24T00:00:00Z","timestamp":1614124800000}}],"reference-count":93,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"crossref","award":["R01GM104279"],"award-info":[{"award-number":["R01GM104279"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM104279 and R01GM067848"],"award-info":[{"award-number":["R01GM104279 and R01GM067848"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Independent Administrative Corporation Japan Student Service Organization","award":["Tobitate Ryugaku JAPAN Nihondaihyou Program"],"award-info":[{"award-number":["Tobitate Ryugaku JAPAN Nihondaihyou Program"]}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    level is under strict regulation through calcium channels and storage pools including the endoplasmic reticulum (ER). Mutations in certain ion channel subunits, which cause mis-regulated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx, induce the excitotoxic necrosis of neurons. In the nematode\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    , dominant mutations in the DEG\/ENaC sodium channel subunit MEC-4 induce six mechanosensory (touch) neurons to undergo excitotoxic necrosis. These necrotic neurons are subsequently engulfed and digested by neighboring hypodermal cells. We previously reported that necrotic touch neurons actively expose phosphatidylserine (PS), an \u201ceat-me\u201d signal, to attract engulfing cells. However, the upstream signal that triggers PS externalization remained elusive. Here we report that a robust and transient increase of cytoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    level occurs prior to the exposure of PS on necrotic touch neurons. Inhibiting the release of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    from the ER, either pharmacologically or genetically, specifically impairs PS exposure on necrotic but not apoptotic cells. On the contrary, inhibiting the reuptake of cytoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    into the ER induces ectopic necrosis and PS exposure. Remarkably, PS exposure occurs independently of other necrosis events. Furthermore, unlike in mutants of DEG\/ENaC channels, in dominant mutants of\n                    <jats:italic>deg-3<\/jats:italic>\n                    and\n                    <jats:italic>trp-4<\/jats:italic>\n                    , which encode Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channels, PS exposure on necrotic neurons does not rely on the ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    pool. Our findings indicate that high levels of cytoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    are necessary and sufficient for PS exposure. They further reveal two Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -dependent, necrosis-specific pathways that promote PS exposure, a \u201ctwo-step\u201d pathway initiated by a modest influx of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    and further boosted by the release of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    from the ER, and another, ER-independent, pathway. Moreover, we found that ANOH-1, the worm homolog of mammalian phospholipid scramblase TMEM16F, is necessary for efficient PS exposure in thapsgargin-treated worms and\n                    <jats:italic>trp-4<\/jats:italic>\n                    mutants, like in\n                    <jats:italic>mec-4<\/jats:italic>\n                    mutants. We propose that both the ER-mediated and ER-independent Ca\n                    <jats:sup>2+<\/jats:sup>\n                    pathways promote PS externalization through activating ANOH-1.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1009066","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T15:03:52Z","timestamp":1613142232000},"page":"e1009066","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":28,"title":["Calcium ions trigger the exposure of phosphatidylserine on the surface of necrotic cells"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1043-1747","authenticated-orcid":true,"given":"Yoshitaka","family":"Furuta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Pena-Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8961-0048","authenticated-orcid":true,"given":"Lucia","family":"Chiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2585-0418","authenticated-orcid":true,"given":"Zheng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,11]]},"reference":[{"key":"pgen.1009066.ref001","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.tibs.2006.11.001","article-title":"Cell 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