{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T22:31:19Z","timestamp":1790289079432,"version":"4.1.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2015,11,1]],"date-time":"2015-11-01T00:00:00Z","timestamp":1446336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>NK cell\u2019s killing is a tightly regulated process under the control of specific cytoskeletal proteins. This includes Wiskott\u2013Aldrich syndrome protein, Wiskott\u2013Aldrich syndrome protein\u2013interacting protein, cofilin, Munc13-4, and nonmuscle myosin IIA (NMIIA). These proteins play a key role in controlling NK-mediated cytotoxicity either via regulating the attachment of lytic granules to the actin-based cytoskeleton or via promoting the cytoskeletal reorganization that is requisite for lytic granule release. UNC-45A is a highly conserved member of the UNC-45\/CRO1\/She4p family of proteins that act as chaperones for both conventional and nonconventional myosin. Although we and others have shown that in lower organisms and in mammalian cells NMIIA-associated functions, such as cytokinesis, cell motility, and organelle trafficking, are dependent upon the presence of UNC-45A, its role in NK-mediated functions is largely unknown. In this article, we describe UNC-45A as a key regulator of NK-mediated cell toxicity. Specifically we show that, in human NK cells, UNC-45A localize at the NK cell immunological synapse of activated NK cells and is part of the multiprotein complex formed during NK cell activation. Furthermore, we show that UNC-45A is disposable for NK cell immunological synapse formation and lytic granules reorientation but crucial for lytic granule exocytosis. Lastly, loss of UNC-45A leads to reduced NMIIA binding to actin, suggesting that UNC-45A is a crucial component in regulating human NK cell cytoskeletal dynamics via promoting the formation of actomyosin complexes.<\/jats:p>","DOI":"10.4049\/jimmunol.1500979","type":"journal-article","created":{"date-parts":[[2015,10,6]],"date-time":"2015-10-06T02:28:22Z","timestamp":1444098502000},"page":"4760-4770","source":"Crossref","is-referenced-by-count":33,"title":["UNC-45A Is a Nonmuscle Myosin IIA Chaperone Required for NK Cell Cytotoxicity via Control of Lytic Granule Secretion"],"prefix":"10.1093","volume":"195","author":[{"given":"Yoshie","family":"Iizuka","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology and Women\u2019s Heath, University of Minnesota Twin Cities , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Cichocki","sequence":"additional","affiliation":[{"name":"Hematology, Oncology and Transplantation, University of Minnesota , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Sieben","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Women\u2019s Heath, University of Minnesota Twin Cities , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Sforza","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, University of Ferrara , 44121 Ferrara ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Razaul","family":"Karim","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Minnesota , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Coughlin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Women\u2019s Heath, University of Minnesota Twin Cities , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Isaksson Vogel","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Women\u2019s Heath, University of Minnesota Twin Cities , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Gavioli","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, University of Ferrara , 44121 Ferrara ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valarie","family":"McCullar","sequence":"additional","affiliation":[{"name":"Hematology, Oncology and Transplantation, University of Minnesota , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Lenvik","sequence":"additional","affiliation":[{"name":"Hematology, Oncology and Transplantation, University of Minnesota , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Minnesota , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Miller","sequence":"additional","affiliation":[{"name":"Hematology, Oncology and Transplantation, University of Minnesota , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Bazzaro","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Women\u2019s Heath, University of Minnesota Twin Cities , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,11,15]]},"reference":[{"key":"2025030704222121800_r1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/j.1600-065X.1997.tb00944.x","article-title":"Human NK cells: their ligands, receptors and functions","volume":"155","author":"Reyburn","year":"1997","journal-title":"Immunol. Rev."},{"key":"2025030704222121800_r2","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1084\/jem.20071143","article-title":"Myosin IIA is required for cytolytic granule exocytosis in human NK cells","volume":"204","author":"Andzelm","year":"2007","journal-title":"J. Exp. Med."},{"key":"2025030704222121800_r3","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1083\/jcb.200509076","article-title":"Formation of a WIP-, WASp-, actin-, and myosin IIA-containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling","volume":"173","author":"Krzewski","year":"2006","journal-title":"J. Cell Biol."},{"key":"2025030704222121800_r4","doi-asserted-by":"crossref","first-page":"14151","DOI":"10.1073\/pnas.1835830100","article-title":"The mature activating natural killer cell immunologic synapse is formed in distinct stages","volume":"100","author":"Orange","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030704222121800_r5","doi-asserted-by":"crossref","first-page":"7767","DOI":"10.1073\/pnas.1336920100","article-title":"Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing","volume":"100","author":"Wulfing","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030704222121800_r6","doi-asserted-by":"crossref","first-page":"6708","DOI":"10.1073\/pnas.1314975111","article-title":"Lytic immune synapse function requires filamentous actin deconstruction by Coronin 1A","volume":"111","author":"Mace","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030704222121800_r7","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1083\/jcb.201407130","article-title":"TAGLN2 regulates T cell activation by stabilizing the actin cytoskeleton at the immunological synapse","volume":"209","author":"Na","year":"2015","journal-title":"J. Cell Biol."},{"key":"2025030704222121800_r8","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.tcb.2007.08.005","article-title":"WASP-interacting protein (WIP): working in polymerisation and much more","volume":"17","author":"Ant\u00f3n","year":"2007","journal-title":"Trends Cell Biol."},{"key":"2025030704222121800_r9","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1182\/blood-2011-02-339523","article-title":"The munc13-4-rab27 complex is specifically required for tethering secretory lysosomes at the plasma membrane","volume":"118","author":"Elstak","year":"2011","journal-title":"Blood"},{"key":"2025030704222121800_r10","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S1074-7613(02)00268-6","article-title":"WIP deficiency reveals a differential role for WIP and the actin cytoskeleton in T and B cell activation","volume":"16","author":"Ant\u00f3n","year":"2002","journal-title":"Immunity"},{"key":"2025030704222121800_r11","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1084\/jem.20131131","article-title":"Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency","volume":"211","author":"Cichocki","year":"2014","journal-title":"J. Exp. Med."},{"key":"2025030704222121800_r12","doi-asserted-by":"crossref","first-page":"5783","DOI":"10.1182\/blood-2011-07-369090","article-title":"Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D","volume":"118","author":"Meeths","year":"2011","journal-title":"Blood"},{"key":"2025030704222121800_r13","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1242\/jcs.087320","article-title":"The myosin-binding UCS domain but not the Hsp90-binding TPR domain of the UNC-45 chaperone is essential for function in Caenorhabditis elegans","volume":"124","author":"Ni","year":"2011","journal-title":"J. Cell Sci."},{"key":"2025030704222121800_r14","doi-asserted-by":"crossref","first-page":"4013","DOI":"10.1242\/jcs.00108","article-title":"Two mammalian UNC-45 isoforms are related to distinct cytoskeletal and muscle-specific functions","volume":"115","author":"Price","year":"2002","journal-title":"J. Cell Sci."},{"key":"2025030704222121800_r15","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.jmb.2011.07.012","article-title":"Differential turnover of myosin chaperone UNC-45A isoforms increases in metastatic human breast cancer","volume":"412","author":"Guo","year":"2011","journal-title":"J. Mol. Biol."},{"key":"2025030704222121800_r16","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.cell.2004.07.014","article-title":"Regulation of the myosin-directed chaperone UNC-45 by a novel E3\/E4-multiubiquitylation complex in C. elegans","volume":"118","author":"Hoppe","year":"2004","journal-title":"Cell"},{"key":"2025030704222121800_r17","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1083\/jcb.143.5.1215","article-title":"Unc-45 mutations in Caenorhabditis elegans implicate a CRO1\/She4p-like domain in myosin assembly","volume":"143","author":"Barral","year":"1998","journal-title":"J. Cell Biol."},{"key":"2025030704222121800_r18","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/B978-0-12-800177-6.00004-9","article-title":"The UNC-45 myosin chaperone: from worms to flies to vertebrates","volume":"313","author":"Lee","year":"2014","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"2025030704222121800_r19","doi-asserted-by":"crossref","first-page":"21382","DOI":"10.1073\/pnas.1013038107","article-title":"UNC-45\/CRO1\/She4p (UCS) protein forms elongated dimer and joins two myosin heads near their actin binding region","volume":"107","author":"Shi","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030704222121800_r20","doi-asserted-by":"crossref","first-page":"6062","DOI":"10.1073\/pnas.0400782101","article-title":"A gene atlas of the mouse and human protein-encoding transcriptomes","volume":"101","author":"Su","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030704222121800_r21","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/978-1-60761-362-6_19","article-title":"Identification of NK cell receptor ligands using a signaling reporter system","volume":"612","author":"Iizuka","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"2025030704222121800_r22","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.4049\/jimmunol.0804337","article-title":"Myosin IIA associates with NK cell lytic granules to enable their interaction with F-actin and function at the immunological synapse","volume":"182","author":"Sanborn","year":"2009","journal-title":"J. Immunol."},{"key":"2025030704222121800_r23","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.1002\/eji.201040444","article-title":"IQGAP1 involvement in MTOC and granule polarization in NK-cell cytotoxicity","volume":"41","author":"Kanwar","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"2025030704222121800_r24","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1182\/blood-2004-10-4100","article-title":"Arf6: a new player in FcgammaRIIIA lymphocyte-mediated cytotoxicity","volume":"106","author":"Galandrini","year":"2005","journal-title":"Blood"},{"key":"2025030704222121800_r25","doi-asserted-by":"crossref","first-page":"35557","DOI":"10.1074\/jbc.M405319200","article-title":"Mechanism of blebbistatin inhibition of myosin II","volume":"279","author":"Kov\u00e1cs","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2025030704222121800_r26","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/nsmb908","article-title":"The structural basis of blebbistatin inhibition and specificity for myosin II","volume":"12","author":"Allingham","year":"2005","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2025030704222121800_r27","doi-asserted-by":"crossref","first-page":"5862","DOI":"10.1182\/blood-2011-03-344846","article-title":"Phosphorylation of the myosin IIA tailpiece regulates single myosin IIA molecule association with lytic granules to promote NK-cell cytotoxicity","volume":"118","author":"Sanborn","year":"2011","journal-title":"Blood"},{"key":"2025030704222121800_r28","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/978-1-60761-362-6_9","article-title":"Analysis of the NK cell immunological synapse","volume":"612","author":"Sanborn","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"2025030704222121800_r29","doi-asserted-by":"crossref","first-page":"14832","DOI":"10.1021\/bi0490284","article-title":"Kinetic mechanism of blebbistatin inhibition of nonmuscle myosin IIb","volume":"43","author":"Ramamurthy","year":"2004","journal-title":"Biochemistry"},{"key":"2025030704222121800_r30","doi-asserted-by":"crossref","first-page":"28856","DOI":"10.1074\/jbc.M114.587527","article-title":"Interactions with actin monomers, actin filaments, and Arp2\/3 complex define the roles of WASP family proteins and cortactin in coordinately regulating branched actin networks","volume":"289","author":"Helgeson","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2025030704222121800_r31","doi-asserted-by":"crossref","first-page":"150","DOI":"10.4049\/jimmunol.1302923","article-title":"Nuclear role of WASp in gene transcription is uncoupled from its ARP2\/3-dependent cytoplasmic role in actin polymerization","volume":"193","author":"Sadhukhan","year":"2014","journal-title":"J. Immunol."},{"key":"2025030704222121800_r32","doi-asserted-by":"crossref","first-page":"2600","DOI":"10.1128\/MCB.00017-14","article-title":"Binding of the WASP\/N-WASP-interacting protein WIP to actin regulates focal adhesion assembly and adhesion","volume":"34","author":"Ramesh","year":"2014","journal-title":"Mol. Cell. Biol."},{"key":"2025030704222121800_r33","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1126\/science.282.5397.2266","article-title":"A receptor\/cytoskeletal movement triggered by costimulation during T cell activation","volume":"282","author":"W\u00fclfing","year":"1998","journal-title":"Science"},{"key":"2025030704222121800_r34","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/35074551","article-title":"WIP regulates N-WASP-mediated actin polymerization and filopodium formation","volume":"3","author":"Martinez-Quiles","year":"2001","journal-title":"Nat. Cell Biol."},{"key":"2025030704222121800_r35","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/35017080","article-title":"A complex of N-WASP and WIP integrates signalling cascades that lead to actin polymerization","volume":"2","author":"Moreau","year":"2000","journal-title":"Nat. Cell Biol."},{"key":"2025030704222121800_r36","doi-asserted-by":"crossref","first-page":"14671","DOI":"10.1073\/pnas.94.26.14671","article-title":"WIP, a protein associated with wiskott-aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells","volume":"94","author":"Ramesh","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030704222121800_r37","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.cub.2013.04.051","article-title":"WIP provides an essential link between Nck and N-WASP during Arp2\/3-dependent actin polymerization","volume":"23","author":"Donnelly","year":"2013","journal-title":"Curr. Biol."},{"key":"2025030704222121800_r38","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1136\/jmg.2010.085456","article-title":"Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis type 3","volume":"48","author":"Sieni","year":"2011","journal-title":"J. Med. Genet."},{"key":"2025030704222121800_r39","doi-asserted-by":"crossref","first-page":"4117","DOI":"10.1182\/blood-2009-06-225359","article-title":"Different NK cell-activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity","volume":"114","author":"Wood","year":"2009","journal-title":"Blood"},{"key":"2025030704222121800_r40","doi-asserted-by":"crossref","first-page":"3765","DOI":"10.1172\/JCI40732","article-title":"Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells","volume":"119","author":"C\u00f4te","year":"2009","journal-title":"J. Clin. Invest."},{"key":"2025030704222121800_r41","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1002\/pbc.23253","article-title":"A novel Dutch mutation in UNC13D reveals an essential role of the C2B domain in munc13-4 function","volume":"58","author":"Elstak","year":"2012","journal-title":"Pediatr. Blood Cancer"},{"key":"2025030704222121800_r42","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1126\/science.1066648","article-title":"Role of the myosin assembly protein UNC-45 as a molecular chaperone for myosin","volume":"295","author":"Barral","year":"2002","journal-title":"Science"},{"key":"2025030704222121800_r43","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/S0960-9822(03)00264-1","article-title":"The UCS domain protein She4p binds to myosin motor domains and is essential for class I and class V myosin function","volume":"13","author":"Wesche","year":"2003","journal-title":"Curr. Biol."},{"key":"2025030704222121800_r44","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.2353\/ajpath.2007.070325","article-title":"Myosin II co-chaperone general cell UNC-45 overexpression is associated with ovarian cancer, rapid proliferation, and motility","volume":"171","author":"Bazzaro","year":"2007","journal-title":"Am. J. Pathol."},{"key":"2025030704222121800_r45","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1182\/blood-2012-07-441832","article-title":"Surface CD107a\/LAMP-1 protects natural killer cells from degranulation-associated damage","volume":"122","author":"Cohnen","year":"2013","journal-title":"Blood"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/10\/4760\/62248605\/1500979.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/10\/4760\/62248605\/1500979.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T05:16:56Z","timestamp":1741324616000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/195\/10\/4760\/7961503"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11]]},"references-count":45,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2015,11,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1500979","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,11]]},"published":{"date-parts":[[2015,11]]}}}