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PI3K signaling of autophagy is required for starvation tolerance and virulenceof Cryptococcus neoformans
| Title: | PI3K signaling of autophagy is required for starvation tolerance and virulenceof Cryptococcus neoformans |
| Authors: | Hu, Guowu Browse this author | | Hacham, Moshe Browse this author | | Waterman, Scott R. Browse this author | | Panepinto, John Browse this author | | Shin, Soowan Browse this author | | Liu, Xiaoguang Browse this author | | Gibbons, Jack Browse this author | | Valyi-Nagy, Tibor Browse this author | | Obara, Keisuke Browse this author | | Jaffe, H. Ari Browse this author | | Ohsumi, Yoshinori Browse this author | | Williamson, Peter R. Browse this author |
| Issue Date: | Mar-2008 |
| Publisher: | American Society for Clinical Investigation |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 118 |
| Issue: | 3 |
| Start Page: | 1186 |
| End Page: | 1197 |
| Publisher DOI: | 10.1172/JCI32053 |
| Abstract: | Autophagy is a process by which cells recycle cytoplasm and defective organelles during stress situations such as nutrient starvation. It can also be used by host cells as an immune defense mechanism to eliminate infectious pathogens. Here we describe the use of autophagy as a survival mechanism and virulence-associated trait by the human fungal pathogen Cryptococcus neoformans. We report that a mutant form of C. neoformans lacking the Vps34 PI3K (vps34Δ), which is known to be involved in autophagy in ascomycete yeast, was defective in the formation of autophagy-related 8–labeled (Atg8-labeled) vesicles and showed a dramatic attenuation in virulence in mouse models of infection. In addition, autophagic vesicles were observed in WT but not vps34Δ cells after phagocytosis by a murine macrophage cell line, and Atg8 expression was exhibited in WT C. neoformans during human infection of brain. To dissect the contribution of defective autophagy in vps34Δ C. neoformans during pathogenesis, a strain of C. neoformans in which Atg8 expression was knocked down by RNA interference was constructed and these fungi also demonstrated markedly attenuated virulence in a mouse model of infection. These results demonstrated PI3K signaling and autophagy as a virulence-associated trait and survival mechanism during infection with a fungal pathogen. Moreover, the data show that molecular dissection of such pathogen stress-response pathways may identify new approaches for chemotherapeutic interventions. |
| Type: | article |
| URI: | http://hdl.handle.net/2115/45459 |
| Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 小原 圭介
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