Unraveling the Pathobiological Role of the Fungal KEOPS Complex in Cryptococcus neoformans
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 neo...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-12-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02944-22 |
| _version_ | 1811196219995717632 |
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| author | Yeseul Choi Eunji Jeong Dong-Gi Lee Jae-Hyung Jin Yee-Seul So Seong-Ryong Yu Kyung-Jo Lee Yoonjie Ha Chi-Jan Lin Ying-Lien Chen Jun Bae Park Hyun-Soo Cho Anna F. Averette Joseph Heitman Kyu-Ho Lee Kangseok Lee Yong-Sun Bahn |
| author_facet | Yeseul Choi Eunji Jeong Dong-Gi Lee Jae-Hyung Jin Yee-Seul So Seong-Ryong Yu Kyung-Jo Lee Yoonjie Ha Chi-Jan Lin Ying-Lien Chen Jun Bae Park Hyun-Soo Cho Anna F. Averette Joseph Heitman Kyu-Ho Lee Kangseok Lee Yong-Sun Bahn |
| author_sort | Yeseul Choi |
| collection | DOAJ |
| description | 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 t6A 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. |
| first_indexed | 2024-04-12T00:56:02Z |
| format | Article |
| id | doaj.art-be58f2538d9840a9b0c563fe73daf2e5 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-12T00:56:02Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-be58f2538d9840a9b0c563fe73daf2e52022-12-22T03:54:37ZengAmerican Society for MicrobiologymBio2150-75112022-12-0113610.1128/mbio.02944-22Unraveling the Pathobiological Role of the Fungal KEOPS Complex in Cryptococcus neoformansYeseul Choi0Eunji Jeong1Dong-Gi Lee2Jae-Hyung Jin3Yee-Seul So4Seong-Ryong Yu5Kyung-Jo Lee6Yoonjie Ha7Chi-Jan Lin8Ying-Lien Chen9Jun Bae Park10Hyun-Soo Cho11Anna F. Averette12Joseph Heitman13Kyu-Ho Lee14Kangseok Lee15Yong-Sun Bahn16Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South KoreaDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South KoreaDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South KoreaDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South KoreaDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South KoreaDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South KoreaDepartment of Life Science, College of Natural Science, Sogang University, Seoul, South KoreaDepartment of Life Science, Chung-Ang University, Seoul, South KoreaDepartment of Plant Pathology and Microbiology, National Taiwan University, Taipei, TaiwanDepartment of Plant Pathology and Microbiology, National Taiwan University, Taipei, TaiwanDepartment of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South KoreaDepartment of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South KoreaDepartment of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USADepartment of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USADepartment of Life Science, College of Natural Science, Sogang University, Seoul, South KoreaDepartment of Life Science, Chung-Ang University, Seoul, South KoreaDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South KoreaABSTRACT 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 t6A 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.https://journals.asm.org/doi/10.1128/mbio.02944-22Bud32Cgi121Kae1Pcc1 |
| spellingShingle | Yeseul Choi Eunji Jeong Dong-Gi Lee Jae-Hyung Jin Yee-Seul So Seong-Ryong Yu Kyung-Jo Lee Yoonjie Ha Chi-Jan Lin Ying-Lien Chen Jun Bae Park Hyun-Soo Cho Anna F. Averette Joseph Heitman Kyu-Ho Lee Kangseok Lee Yong-Sun Bahn Unraveling the Pathobiological Role of the Fungal KEOPS Complex in Cryptococcus neoformans mBio Bud32 Cgi121 Kae1 Pcc1 |
| title | Unraveling the Pathobiological Role of the Fungal KEOPS Complex in Cryptococcus neoformans |
| title_full | Unraveling the Pathobiological Role of the Fungal KEOPS Complex in Cryptococcus neoformans |
| title_fullStr | Unraveling the Pathobiological Role of the Fungal KEOPS Complex in Cryptococcus neoformans |
| title_full_unstemmed | Unraveling the Pathobiological Role of the Fungal KEOPS Complex in Cryptococcus neoformans |
| title_short | Unraveling the Pathobiological Role of the Fungal KEOPS Complex in Cryptococcus neoformans |
| title_sort | unraveling the pathobiological role of the fungal keops complex in cryptococcus neoformans |
| topic | Bud32 Cgi121 Kae1 Pcc1 |
| url | https://journals.asm.org/doi/10.1128/mbio.02944-22 |
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