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Cryptococcal Kcs1 converts IP<jats:sub>6<\/jats:sub> to PP-IP<jats:sub>5<\/jats:sub>\/IP<jats:sub>7<\/jats:sub>, but the kinase converting IP<jats:sub>5<\/jats:sub> to IP<jats:sub>6<\/jats:sub> is unknown. Deletion of a putative IP<jats:sub>5<\/jats:sub> kinase-encoding gene (<jats:italic>IPK1<\/jats:italic>) alone (<jats:italic>ipk1<\/jats:italic>\u0394) and in combination with <jats:italic>KCS1<\/jats:italic> (<jats:italic>ipk1<\/jats:italic>\u0394<jats:italic>kcs1<\/jats:italic>\u0394), profoundly reduced virulence in mice. However, deletion of <jats:italic>KCS1<\/jats:italic> and <jats:italic>IPK1<\/jats:italic> had a greater impact on virulence attenuation than that of <jats:italic>IPK1<\/jats:italic> alone. <jats:italic>ipk1<\/jats:italic>\u0394<jats:italic>kcs1<\/jats:italic>\u0394 and <jats:italic>kcs1<\/jats:italic>\u0394 lung burdens were also lower than those of <jats:italic>ipk1<\/jats:italic>\u0394. Unlike <jats:italic>ipk1<\/jats:italic>\u0394, <jats:italic>ipk1<\/jats:italic>\u0394<jats:italic>kcs1<\/jats:italic>\u0394 and <jats:italic>kcs1<\/jats:italic>\u0394 failed to disseminate to the brain. IP profiling confirmed Ipk1 as the major IP<jats:sub>5<\/jats:sub> kinase in <jats:italic>C. neoformans<\/jats:italic>: <jats:italic>ipk1<\/jats:italic>\u0394 produced no IP<jats:sub>6<\/jats:sub> or PP-IP<jats:sub>5<\/jats:sub>\/IP<jats:sub>7<\/jats:sub> and, in contrast to <jats:italic>ipk1<\/jats:italic>\u0394<jats:italic>kcs1<\/jats:italic>\u0394, accumulated IP<jats:sub>5<\/jats:sub> and its pyrophosphorylated PP-IP<jats:sub>4<\/jats:sub> derivative. Kcs1 is therefore a dual specificity (IP<jats:sub>5<\/jats:sub> and IP<jats:sub>6<\/jats:sub>) kinase producing PP-IP<jats:sub>4<\/jats:sub> and PP-IP<jats:sub>5<\/jats:sub>\/IP<jats:sub>7<\/jats:sub>. All mutants were similarly attenuated in virulence phenotypes including laccase, urease and growth under oxidative\/nitrosative stress. Alternative carbon source utilisation was also reduced significantly in all mutants except <jats:italic>ipk1<\/jats:italic>\u0394, suggesting that PP-IP<jats:sub>4<\/jats:sub> partially compensates for absent PP-IP<jats:sub>5<\/jats:sub>\/IP<jats:sub>7<\/jats:sub> in <jats:italic>ipk1<\/jats:italic>\u0394 grown under this condition. In conclusion, PP-IP<jats:sub>5<\/jats:sub>\/IP<jats:sub>7<\/jats:sub>, not IP<jats:sub>6<\/jats:sub>, is essential for fungal virulence.<\/jats:p>","DOI":"10.1038\/srep23927","type":"journal-article","created":{"date-parts":[[2016,4,1]],"date-time":"2016-04-01T09:04:43Z","timestamp":1459501483000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Identification of a major IP5 kinase in Cryptococcus neoformans confirms that PP-IP5\/IP7, not IP6, is essential for virulence"],"prefix":"10.1038","volume":"6","author":[{"given":"Cecilia","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Lev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo","family":"Saiardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desmarini","family":"Desmarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania C.","family":"Sorrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julianne T.","family":"Djordjevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,1]]},"reference":[{"key":"BFsrep23927_CR1","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1097\/QAD.0b013e328322ffac","volume":"23","author":"BJ Park","year":"2009","unstructured":"Park, B. 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