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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,3,26]]},"abstract":"<jats:p>\n                    Apicomplexan parasites replicate within a protective organelle, called the parasitophorous vacuole (PV). The\n                    <jats:italic>Toxoplasma gondii<\/jats:italic>\n                    PV is filled with a network of tubulated membranes, which are thought to facilitate trafficking of effectors and nutrients. Despite being critical to parasite virulence, there is scant mechanistic understanding of the network\u2019s functions. Here, we identify the parasite-secreted kinase WNG1 (With-No-Gly-loop) as a critical regulator of tubular membrane biogenesis. WNG1 family members adopt an atypical protein kinase fold lacking the glycine rich ATP-binding loop that is required for catalysis in canonical kinases. Unexpectedly, we find that WNG1 is an active protein kinase that localizes to the PV lumen and phosphorylates PV-resident proteins, several of which are essential for the formation of a functional intravacuolar network. Moreover, we show that WNG1-dependent phosphorylation of these proteins is required for their membrane association, and thus their ability to tubulate membranes. Consequently, WNG1 knockout parasites have an aberrant PV membrane ultrastructure. Collectively, our results describe a unique family of\n                    <jats:italic>Toxoplasma<\/jats:italic>\n                    kinases and implicate phosphorylation of secreted proteins as a mechanism of regulating PV development during parasite infection.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1816161116","type":"journal-article","created":{"date-parts":[[2019,3,8]],"date-time":"2019-03-08T20:36:59Z","timestamp":1552077419000},"page":"6361-6370","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":55,"title":["Divergent kinase regulates membrane ultrastructure of the\n                    <i>Toxoplasma<\/i>\n                    parasitophorous vacuole"],"prefix":"10.1073","volume":"116","author":[{"given":"Tsebaot","family":"Beraki","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Broncel","sequence":"additional","affiliation":[{"name":"Signalling in Apicomplexan Parasites Laboratory, The Francis Crick Institute, NW1 1AT London United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna C.","family":"Young","sequence":"additional","affiliation":[{"name":"Signalling in Apicomplexan Parasites Laboratory, The Francis Crick Institute, NW1 1AT London United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"O\u2019Shaughnessy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX 75390;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4321-6253","authenticated-orcid":false,"given":"Dominika","family":"Borek","sequence":"additional","affiliation":[{"name":"Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390;"},{"name":"Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9727-6657","authenticated-orcid":false,"given":"Moritz","family":"Treeck","sequence":"additional","affiliation":[{"name":"Signalling in Apicomplexan Parasites Laboratory, The Francis Crick Institute, NW1 1AT London United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9401-9594","authenticated-orcid":false,"given":"Michael L.","family":"Reese","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX 75390;"},{"name":"Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,3,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1126\/science.1075762","article-title":"The protein kinase complement of the human genome","volume":"298","author":"Manning G","year":"2002","unstructured":"G Manning, DB Whyte, R Martinez, T Hunter, S Sudarsanam, The protein kinase complement of the human genome. Science 298, 1912\u20131934 (2002).","journal-title":"Science"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/j.ijpara.2009.04.003","article-title":"Toxoplasmosis snapshots: Global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis","volume":"39","author":"Pappas G","year":"2009","unstructured":"G Pappas, N Roussos, ME Falagas, Toxoplasmosis snapshots: Global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis. Int J Parasitol 39, 1385\u20131394 (2009).","journal-title":"Int J Parasitol"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/nrmicro1800","article-title":"Kiss and spit: The dual roles of Toxoplasma rhoptries","volume":"6","author":"Boothroyd JC","year":"2008","unstructured":"JC Boothroyd, J-F Dubremetz, Kiss and spit: The dual roles of Toxoplasma rhoptries. Nat Rev Microbiol 6, 79\u201388 (2008).","journal-title":"Nat Rev Microbiol"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1128\/CMR.00005-17","article-title":"Toxoplasma effectors targeting host signaling and transcription","volume":"30","author":"Hakimi M-A","year":"2017","unstructured":"M-A Hakimi, P Olias, LD Sibley, Toxoplasma effectors targeting host signaling and transcription. Clin Microbiol Rev 30, 615\u2013645 (2017).","journal-title":"Clin Microbiol Rev"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.chom.2010.07.004","article-title":"Integrative genomic approaches highlight a family of parasite-specific kinases that regulate host responses","volume":"8","author":"Peixoto L","year":"2010","unstructured":"L Peixoto, , Integrative genomic approaches highlight a family of parasite-specific kinases that regulate host responses. 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Mamm Genome 22, 43\u201354 (2011).","journal-title":"Mamm Genome"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"e1006027","DOI":"10.1371\/journal.ppat.1006027","article-title":"K63-linked ubiquitination targets Toxoplasma gondii for endo-lysosomal destruction in IFN\u03b3-stimulated human cells","volume":"12","author":"Clough B","year":"2016","unstructured":"B Clough, , K63-linked ubiquitination targets Toxoplasma gondii for endo-lysosomal destruction in IFN\u03b3-stimulated human cells. 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Cell Host Microbe 17, 642\u2013652 (2015).","journal-title":"Cell Host Microbe"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1242\/jcs.108.4.1669","article-title":"Regulated secretion of multi-lamellar vesicles leads to formation of a tubulo-vesicular network in host-cell vacuoles occupied by Toxoplasma gondii","volume":"108","author":"Sibley LD","year":"1995","unstructured":"LD Sibley, IR Niesman, SF Parmley, MF Cesbron-Delauw, Regulated secretion of multi-lamellar vesicles leads to formation of a tubulo-vesicular network in host-cell vacuoles occupied by Toxoplasma gondii. 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Cell 125, 261\u2013274 (2006).","journal-title":"Cell"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1091\/mbc.e12-11-0827","article-title":"Toxoplasma gondii salvages sphingolipids from the host Golgi through the rerouting of selected Rab vesicles to the parasitophorous vacuole","volume":"24","author":"Romano JD","year":"2013","unstructured":"JD Romano, S Sonda, E Bergbower, ME Smith, I Coppens, Toxoplasma gondii salvages sphingolipids from the host Golgi through the rerouting of selected Rab vesicles to the parasitophorous vacuole. 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