A fungal ubiquitin ligase and arrestin binding partner contribute to pathogenesis and survival during cellular stress
ABSTRACT Cellular responses to external stress allow microorganisms to adapt to a vast array of environmental conditions, including infection sites. The molecular mechanisms behind these responses are studied to gain insight into microbial pathogenesis, which could lead to new antimicrobial therapie...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2024-10-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00981-24 |
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| author | Lukas M. du Plooy Calla L. Telzrow Connie B. Nichols Corinna Probst Natalia Castro-Lopez Floyd L. Wormley J. Andrew Alspaugh |
| author_facet | Lukas M. du Plooy Calla L. Telzrow Connie B. Nichols Corinna Probst Natalia Castro-Lopez Floyd L. Wormley J. Andrew Alspaugh |
| author_sort | Lukas M. du Plooy |
| collection | DOAJ |
| description | ABSTRACT Cellular responses to external stress allow microorganisms to adapt to a vast array of environmental conditions, including infection sites. The molecular mechanisms behind these responses are studied to gain insight into microbial pathogenesis, which could lead to new antimicrobial therapies. Here, we explore a role for arrestin protein-mediated ubiquitination in stress response and pathogenesis in the pathogenic fungus Cryptococcus neoformans. In a previous study, we identified four arrestin-like proteins in C. neoformans and found that one of these is required for efficient membrane synthesis, likely by directing interaction between fatty acid synthases and the Rsp5 E3 ubiquitin ligase. Here, we further explore Cn Rsp5 function and determine that this single Ub ligase is absolutely required for pathogenesis and survival in the presence of cellular stress. Additionally, we show that a second arrestin-like protein, Ali2, similarly facilitates interaction between Rsp5 and some of its protein targets. Of the four postulated C. neoformans arrestin-like proteins, Ali2 appears to contribute the most to C. neoformans pathogenesis, likely by directing Rsp5 to pathogenesis-related ubiquitination targets. A proteomics-based differential ubiquitination screen revealed that several known cell surface proteins are ubiquitinated by Rsp5 and a subset also requires Ali2 for their ubiquitination. Rsp5-mediated ubiquitination alters the stability and the localization of these proteins. A loss of Rsp5-mediated ubiquitination results in cell wall defects that increase susceptibility to external stresses. These findings support a model in which arrestin-like proteins guide Rsp5 to ubiquitinate specific target proteins, some of which are required for survival during stress.IMPORTANCEMicrobial proteins involved in human infectious diseases often need to be modified by specific chemical additions to be fully functional. Here, we explore the role of a particular protein modification, ubiquitination, in infections due to the human fungal pathogen Cryptococcus neoformans. We identified a complex of proteins responsible for adding ubiquitin groups to fungal proteins, and this complex is required for virulence. These proteins are fungal specific and might be targets for novel anti-infection therapy. |
| format | Article |
| id | doaj-art-6afdb1943cbe404d9dfbeb5018096d34 |
| institution | OA Journals |
| issn | 2150-7511 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-6afdb1943cbe404d9dfbeb5018096d342025-08-20T02:17:06ZengAmerican Society for MicrobiologymBio2150-75112024-10-01151010.1128/mbio.00981-24A fungal ubiquitin ligase and arrestin binding partner contribute to pathogenesis and survival during cellular stressLukas M. du Plooy0Calla L. Telzrow1Connie B. Nichols2Corinna Probst3Natalia Castro-Lopez4Floyd L. Wormley5J. Andrew Alspaugh6Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USADepartment of Medicine, Duke University School of Medicine, Durham, North Carolina, USADepartment of Medicine, Duke University School of Medicine, Durham, North Carolina, USADepartment of Medicine, Duke University School of Medicine, Durham, North Carolina, USADepartment of Biology, University of Texas at San Antonio, San Antonio, Texas, USADepartment of Biology, University of Texas at San Antonio, San Antonio, Texas, USADepartment of Medicine, Duke University School of Medicine, Durham, North Carolina, USAABSTRACT Cellular responses to external stress allow microorganisms to adapt to a vast array of environmental conditions, including infection sites. The molecular mechanisms behind these responses are studied to gain insight into microbial pathogenesis, which could lead to new antimicrobial therapies. Here, we explore a role for arrestin protein-mediated ubiquitination in stress response and pathogenesis in the pathogenic fungus Cryptococcus neoformans. In a previous study, we identified four arrestin-like proteins in C. neoformans and found that one of these is required for efficient membrane synthesis, likely by directing interaction between fatty acid synthases and the Rsp5 E3 ubiquitin ligase. Here, we further explore Cn Rsp5 function and determine that this single Ub ligase is absolutely required for pathogenesis and survival in the presence of cellular stress. Additionally, we show that a second arrestin-like protein, Ali2, similarly facilitates interaction between Rsp5 and some of its protein targets. Of the four postulated C. neoformans arrestin-like proteins, Ali2 appears to contribute the most to C. neoformans pathogenesis, likely by directing Rsp5 to pathogenesis-related ubiquitination targets. A proteomics-based differential ubiquitination screen revealed that several known cell surface proteins are ubiquitinated by Rsp5 and a subset also requires Ali2 for their ubiquitination. Rsp5-mediated ubiquitination alters the stability and the localization of these proteins. A loss of Rsp5-mediated ubiquitination results in cell wall defects that increase susceptibility to external stresses. These findings support a model in which arrestin-like proteins guide Rsp5 to ubiquitinate specific target proteins, some of which are required for survival during stress.IMPORTANCEMicrobial proteins involved in human infectious diseases often need to be modified by specific chemical additions to be fully functional. Here, we explore the role of a particular protein modification, ubiquitination, in infections due to the human fungal pathogen Cryptococcus neoformans. We identified a complex of proteins responsible for adding ubiquitin groups to fungal proteins, and this complex is required for virulence. These proteins are fungal specific and might be targets for novel anti-infection therapy.https://journals.asm.org/doi/10.1128/mbio.00981-24Cryptococcus neoformansarrestinE3 ubiquitin ligasefungal pathogenesis |
| spellingShingle | Lukas M. du Plooy Calla L. Telzrow Connie B. Nichols Corinna Probst Natalia Castro-Lopez Floyd L. Wormley J. Andrew Alspaugh A fungal ubiquitin ligase and arrestin binding partner contribute to pathogenesis and survival during cellular stress mBio Cryptococcus neoformans arrestin E3 ubiquitin ligase fungal pathogenesis |
| title | A fungal ubiquitin ligase and arrestin binding partner contribute to pathogenesis and survival during cellular stress |
| title_full | A fungal ubiquitin ligase and arrestin binding partner contribute to pathogenesis and survival during cellular stress |
| title_fullStr | A fungal ubiquitin ligase and arrestin binding partner contribute to pathogenesis and survival during cellular stress |
| title_full_unstemmed | A fungal ubiquitin ligase and arrestin binding partner contribute to pathogenesis and survival during cellular stress |
| title_short | A fungal ubiquitin ligase and arrestin binding partner contribute to pathogenesis and survival during cellular stress |
| title_sort | fungal ubiquitin ligase and arrestin binding partner contribute to pathogenesis and survival during cellular stress |
| topic | Cryptococcus neoformans arrestin E3 ubiquitin ligase fungal pathogenesis |
| url | https://journals.asm.org/doi/10.1128/mbio.00981-24 |
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