A critical role for staphylococcal nitric oxide synthase in controlling flavohemoglobin toxicity
Most coagulase-negative staphylococcal species, including the opportunistic pathogen Staphylococcus epidermidis, struggle to maintain redox homeostasis and grow under nitrosative stress. Under these conditions, growth can only resume once nitric oxide (NO) is detoxified by the flavohemoglobin Hmp. P...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723003361 |
| _version_ | 1827781826070970368 |
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| author | Ryan M. Singh Sujata S. Chaudhari Sasmita Panda Elizabeth H. Hutfless Cortney E. Heim Dhananjay Shinde Abdulelah A. Alqarzaee Margaret Sladek Vineet Kumar Matthew C. Zimmerman Paul D. Fey Tammy Kielian Vinai C. Thomas |
| author_facet | Ryan M. Singh Sujata S. Chaudhari Sasmita Panda Elizabeth H. Hutfless Cortney E. Heim Dhananjay Shinde Abdulelah A. Alqarzaee Margaret Sladek Vineet Kumar Matthew C. Zimmerman Paul D. Fey Tammy Kielian Vinai C. Thomas |
| author_sort | Ryan M. Singh |
| collection | DOAJ |
| description | Most coagulase-negative staphylococcal species, including the opportunistic pathogen Staphylococcus epidermidis, struggle to maintain redox homeostasis and grow under nitrosative stress. Under these conditions, growth can only resume once nitric oxide (NO) is detoxified by the flavohemoglobin Hmp. Paradoxically, S. epidermidis produces endogenous NO through its genetically encoded nitric oxide synthase (seNOS) and heavily relies on its activity for growth. In this study, we investigate the basis of the growth advantage attributed to seNOS activity. Our findings reveal that seNOS supports growth by countering Hmp toxicity. S. epidermidis relies on Hmp activity for its survival in the host under NO stress. However, in the absence of nitrosative stress, Hmp generates significant amounts of the harmful superoxide radical (O2•-) from its heme prosthetic group which impedes growth. To limit Hmp toxicity, nitrite (NO2−) derived from seNOS promotes CymR-CysK regulatory complex activity, which typically regulates cysteine metabolism, but we now demonstrate to also repress hmp transcription. These findings reveal a critical mechanism through which the bacterial NOS-Hmp axis drives staphylococcal fitness. |
| first_indexed | 2024-03-11T15:23:16Z |
| format | Article |
| id | doaj.art-8d1bfec481d548bda7212dd3f2098cab |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-11T15:23:16Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-8d1bfec481d548bda7212dd3f2098cab2023-10-28T05:07:22ZengElsevierRedox Biology2213-23172023-11-0167102935A critical role for staphylococcal nitric oxide synthase in controlling flavohemoglobin toxicityRyan M. Singh0Sujata S. Chaudhari1Sasmita Panda2Elizabeth H. Hutfless3Cortney E. Heim4Dhananjay Shinde5Abdulelah A. Alqarzaee6Margaret Sladek7Vineet Kumar8Matthew C. Zimmerman9Paul D. Fey10Tammy Kielian11Vinai C. Thomas12Center for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACenter for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACenter for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACenter for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACenter for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACenter for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACenter for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACenter for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACenter for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACenter for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACenter for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USACenter for Staphylococcal Research, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA; Corresponding author. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-6495, USA.Most coagulase-negative staphylococcal species, including the opportunistic pathogen Staphylococcus epidermidis, struggle to maintain redox homeostasis and grow under nitrosative stress. Under these conditions, growth can only resume once nitric oxide (NO) is detoxified by the flavohemoglobin Hmp. Paradoxically, S. epidermidis produces endogenous NO through its genetically encoded nitric oxide synthase (seNOS) and heavily relies on its activity for growth. In this study, we investigate the basis of the growth advantage attributed to seNOS activity. Our findings reveal that seNOS supports growth by countering Hmp toxicity. S. epidermidis relies on Hmp activity for its survival in the host under NO stress. However, in the absence of nitrosative stress, Hmp generates significant amounts of the harmful superoxide radical (O2•-) from its heme prosthetic group which impedes growth. To limit Hmp toxicity, nitrite (NO2−) derived from seNOS promotes CymR-CysK regulatory complex activity, which typically regulates cysteine metabolism, but we now demonstrate to also repress hmp transcription. These findings reveal a critical mechanism through which the bacterial NOS-Hmp axis drives staphylococcal fitness.http://www.sciencedirect.com/science/article/pii/S2213231723003361Staphylococcus epidermidisBacterial nitric oxide synthaseFlavohemoglobinSuperoxideRespiration |
| spellingShingle | Ryan M. Singh Sujata S. Chaudhari Sasmita Panda Elizabeth H. Hutfless Cortney E. Heim Dhananjay Shinde Abdulelah A. Alqarzaee Margaret Sladek Vineet Kumar Matthew C. Zimmerman Paul D. Fey Tammy Kielian Vinai C. Thomas A critical role for staphylococcal nitric oxide synthase in controlling flavohemoglobin toxicity Redox Biology Staphylococcus epidermidis Bacterial nitric oxide synthase Flavohemoglobin Superoxide Respiration |
| title | A critical role for staphylococcal nitric oxide synthase in controlling flavohemoglobin toxicity |
| title_full | A critical role for staphylococcal nitric oxide synthase in controlling flavohemoglobin toxicity |
| title_fullStr | A critical role for staphylococcal nitric oxide synthase in controlling flavohemoglobin toxicity |
| title_full_unstemmed | A critical role for staphylococcal nitric oxide synthase in controlling flavohemoglobin toxicity |
| title_short | A critical role for staphylococcal nitric oxide synthase in controlling flavohemoglobin toxicity |
| title_sort | critical role for staphylococcal nitric oxide synthase in controlling flavohemoglobin toxicity |
| topic | Staphylococcus epidermidis Bacterial nitric oxide synthase Flavohemoglobin Superoxide Respiration |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723003361 |
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