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mBio

Title:		Unraveling the Pathobiological Role of the Fungal KEOPS Complex in Cryptococcus neoformans
Author(s):		Choi Y; Jeong E; Lee DG; Jin JH; So YS; Yu SR; Lee KJ; Ha Y; Lin CJ; Chen YL; Park JB; Cho HS; Averette AF; Heitman J; Lee KH; Lee K; Bahn YS;
Address:		"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei Universitygrid.15444.30, Seoul, South Korea. Department of Life Science, College of Natural Science, Sogang Universitygrid.263736.5, Seoul, South Korea. Department of Life Science, Chung-Ang Universitygrid.254224.7, Seoul, South Korea. Department of Plant Pathology and Microbiology, National Taiwan Universitygrid.19188.39, Taipei, Taiwan. Department of Systems Biology, College of Life Science and Biotechnology, Yonsei Universitygrid.15444.30, Seoul, South Korea. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA"
Journal Title:		mBio
Year:		2022
Volume:		20221115
Issue:		6
Page Number:		e0294422 -
DOI:		10.1128/mbio.02944-22
ISSN/ISBN:		2150-7511 (Electronic)
Abstract:		"The KEOPS (kinase, putative endopeptidase, and other proteins of small size) complex has critical functions in eukaryotes; however, its role in fungal pathogens remains elusive. Herein, we comprehensively analyzed the pathobiological functions of the fungal KEOPS complex in Cryptococcus neoformans (Cn), which causes fatal meningoencephalitis in humans. We identified four CnKEOPS components: Pcc1, Kae1, Bud32, and Cgi121. Deletion of PCC1, KAE1, or BUD32 caused severe defects in vegetative growth, cell cycle control, sexual development, general stress responses, and virulence factor production, whereas deletion of CGI121 led to similar but less severe defects. This suggests that Pcc1, Kae1, and Bud32 are the core KEOPS components, and Cgi121 may play auxiliary roles. Nevertheless, all KEOPS components were essential for C. neoformans pathogenicity. Although the CnKEOPS complex appeared to have a conserved linear arrangement of Pcc1-Kae1-Bud32-Cgi121, as supported by physical interaction between Pcc1-Kae1 and Kae1-Bud32, CnBud32 was found to have a unique extended loop region that was critical for the KEOPS functions. Interestingly, CnBud32 exhibited both kinase activity-dependent and -independent functions. Supporting its pleiotropic roles, the CnKEOPS complex not only played conserved roles in t(6)A modification of ANN codon-recognizing tRNAs but also acted as a major transcriptional regulator, thus controlling hundreds of genes involved in various cellular processes, particularly ergosterol biosynthesis. In conclusion, the KEOPS complex plays both evolutionarily conserved and divergent roles in controlling the pathobiological features of C. neoformans and could be an anticryptococcal drug target. IMPORTANCE The cellular function and structural configuration of the KEOPS complex have been elucidated in some eukaryotes and archaea but have never been fully characterized in fungal pathogens. Here, we comprehensively analyzed the pathobiological roles of the KEOPS complex in the globally prevalent fungal meningitis-causing pathogen C. neoformans. The CnKEOPS complex, composed of a linear arrangement of Pcc1-Kae1-Bud32-Cgi121, not only played evolutionarily conserved roles in growth, sexual development, stress responses, and tRNA modification but also had unique roles in controlling virulence factor production and pathogenicity. Notably, a unique extended loop structure in CnBud32 is critical for the KEOPS complex in C. neoformans. Supporting its pleiotropic roles, transcriptome analysis revealed that the CnKEOPS complex governs several hundreds of genes involved in carbon and amino acid metabolism, pheromone response, and ergosterol biosynthesis. Therefore, this study provides novel insights into the fungal KEOPS complex that could be exploited as a potential antifungal drug target"
Keywords:		Humans *Cryptococcus neoformans/enzymology/metabolism/pathogenicity Ergosterol *Fungal Proteins/genetics/metabolism Phosphotransferases/metabolism Endopeptidases/metabolism Bud32 Cgi121 Kae1 Pcc1;
Notes:		"MedlineChoi, Yeseul Jeong, Eunji Lee, Dong-Gi Jin, Jae-Hyung So, Yee-Seul Yu, Seong-Ryong Lee, Kyung-Jo Ha, Yoonjie Lin, Chi-Jan Chen, Ying-Lien Park, Jun Bae Cho, Hyun-Soo Averette, Anna F Heitman, Joseph Lee, Kyu-Ho Lee, Kangseok Bahn, Yong-Sun eng R01 AI039115/AI/NIAID NIH HHS/ R01 AI050113/AI/NIAID NIH HHS/ R37 AI039115/AI/NIAID NIH HHS/ 2022/11/16 mBio. 2022 Dec 20; 13(6):e0294422. doi: 10.1128/mbio.02944-22. Epub 2022 Nov 15"