Kyung-Tae Lee1,*, Yee-Seul So1,*, Dong-Hoon Yang1,*, Kwang-Woo Jung1,+, Jaeyoung Choi2,+, Dong-Gi Lee3, Hyojeong Kwon1, Juyeong Jang1, Li Li Wang1, Soohyun Cha1, Gena Lee Meyers1, Eunji Jeong1, Jae-Hyung Jin1, Yeonseon Lee1, Joohyeon Hong1, Soohyun Bang1, Je-Hyun Ji1, Goun Park1, Hyo-Jeong Byun1, Sung Woo Park1, Young-Min Park1, Gloria Adedoyin4, Taeyup Kim4, Anna F. Averette4, Jong-Soon Choi3, Joseph Heitman4, Eunji Cheong1, Yong-Hwan Lee2 & Yong-Sun Bahn1
1Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea. 2Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea. 3 Biological Disaster Analysis Group, Korea Basic Science Institute, Daejeon 34133, Korea. 4Departments of Molecular Genetics and Microbiology, Medicine, and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
* These authors contributed equally to this work.
+ Present addresses: Research Division for Biotechnology, Korea Atomic Energy Research Institute, Jeongeup 56212, Korea (K.-W.J.); The Samuel Roberts Noble Foundation, Ardmore, Oklahoma 73401, USA (J.C.).
Correspondence and requests for materials should be addressed to Y.-S.B..
Cryptococcus neoformans is the leading cause of death by fungal meningoencephalitis; however, treatment options remain limited. Here we report the construction of 264 signature-tagged gene-deletion strains for 129 putative kinases, and examine their phenotypic traits under 30 distinct in vitro growth conditions and in two different hosts (insect larvae and mice). Clustering analysis of in vitro phenotypic traits indicates that several of these kinases have roles in known signalling pathways, and identifies hitherto uncharacterized signalling cascades. Virulence assays in the insect and mouse models provide evidence of pathogenicity-related roles for 63 kinases involved in the following biological categories: growth and cell cycle, nutrient metabolism, stress response and adaptation, cell signalling, cell polarity and morphology, vacuole trafficking, transfer RNA (tRNA) modification and other functions. Our study provides insights into the pathobiological signalling circuitry of C. neoformans and identifies potential anticryptococcal or antifungal drug targets.