<italic toggle="yes">Staphylococcus aureus</italic> HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis

ABSTRACT Staphylococcus aureus is responsible for a significant amount of devastating disease. Its ability to colonize the host and cause infection is supported by a variety of proteins that are dependent on the cofactor heme. Heme is a porphyrin used broadly across kingdoms and is synthesized de no...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jacob E. Choby, Caroline M. Grunenwald, Arianna I. Celis, Svetlana Y. Gerdes, Jennifer L. DuBois, Eric P. Skaar
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Staphylococcus aureus heme tetrapyrroles Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/405059706deb49fc97647c9d061a40c4
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:405059706deb49fc97647c9d061a40c4
record_format	dspace
spelling	oai:doaj.org-article:405059706deb49fc97647c9d061a40c42021-11-15T15:53:26Z<italic toggle="yes">Staphylococcus aureus</italic> HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis10.1128/mBio.02287-172150-7511https://doaj.org/article/405059706deb49fc97647c9d061a40c42018-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02287-17https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus is responsible for a significant amount of devastating disease. Its ability to colonize the host and cause infection is supported by a variety of proteins that are dependent on the cofactor heme. Heme is a porphyrin used broadly across kingdoms and is synthesized de novo from common cellular precursors and iron. While heme is critical to bacterial physiology, it is also toxic in high concentrations, requiring that organisms encode regulatory processes to control heme homeostasis. In this work, we describe a posttranscriptional regulatory strategy in S. aureus heme biosynthesis. The first committed enzyme in the S. aureus heme biosynthetic pathway, glutamyl-tRNA reductase (GtrR), is regulated by heme abundance and the integral membrane protein HemX. GtrR abundance increases dramatically in response to heme deficiency, suggesting a mechanism by which S. aureus responds to the need to increase heme synthesis. Additionally, HemX is required to maintain low levels of GtrR in heme-proficient cells, and inactivation of hemX leads to increased heme synthesis. Excess heme synthesis in a ΔhemX mutant activates the staphylococcal heme stress response, suggesting that regulation of heme synthesis is critical to reduce self-imposed heme toxicity. Analysis of diverse organisms indicates that HemX is widely conserved among heme-synthesizing bacteria, suggesting that HemX is a common factor involved in the regulation of GtrR abundance. Together, this work demonstrates that S. aureus regulates heme synthesis by modulating GtrR abundance in response to heme deficiency and through the activity of the broadly conserved HemX. IMPORTANCE Staphylococcus aureus is a leading cause of skin and soft tissue infections, endocarditis, bacteremia, and osteomyelitis, making it a critical health care concern. Development of new antimicrobials against S. aureus requires knowledge of the physiology that supports this organism’s pathogenesis. One component of staphylococcal physiology that contributes to growth and virulence is heme. Heme is a widely utilized cofactor that enables diverse chemical reactions across many enzyme families. S. aureus relies on many critical heme-dependent proteins and is sensitive to excess heme toxicity, suggesting S. aureus must maintain proper intracellular heme homeostasis. Because S. aureus provides heme for heme-dependent enzymes via synthesis from common precursors, we hypothesized that regulation of heme synthesis is one mechanism to maintain heme homeostasis. In this study, we identify that S. aureus posttranscriptionally regulates heme synthesis by restraining abundance of the first heme biosynthetic enzyme, GtrR, via heme and the broadly conserved membrane protein HemX.Jacob E. ChobyCaroline M. GrunenwaldArianna I. CelisSvetlana Y. GerdesJennifer L. DuBoisEric P. SkaarAmerican Society for MicrobiologyarticleStaphylococcus aureushemetetrapyrrolesMicrobiologyQR1-502ENmBio, Vol 9, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus heme tetrapyrroles Microbiology QR1-502
spellingShingle	Staphylococcus aureus heme tetrapyrroles Microbiology QR1-502 Jacob E. Choby Caroline M. Grunenwald Arianna I. Celis Svetlana Y. Gerdes Jennifer L. DuBois Eric P. Skaar <italic toggle="yes">Staphylococcus aureus</italic> HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis
description	ABSTRACT Staphylococcus aureus is responsible for a significant amount of devastating disease. Its ability to colonize the host and cause infection is supported by a variety of proteins that are dependent on the cofactor heme. Heme is a porphyrin used broadly across kingdoms and is synthesized de novo from common cellular precursors and iron. While heme is critical to bacterial physiology, it is also toxic in high concentrations, requiring that organisms encode regulatory processes to control heme homeostasis. In this work, we describe a posttranscriptional regulatory strategy in S. aureus heme biosynthesis. The first committed enzyme in the S. aureus heme biosynthetic pathway, glutamyl-tRNA reductase (GtrR), is regulated by heme abundance and the integral membrane protein HemX. GtrR abundance increases dramatically in response to heme deficiency, suggesting a mechanism by which S. aureus responds to the need to increase heme synthesis. Additionally, HemX is required to maintain low levels of GtrR in heme-proficient cells, and inactivation of hemX leads to increased heme synthesis. Excess heme synthesis in a ΔhemX mutant activates the staphylococcal heme stress response, suggesting that regulation of heme synthesis is critical to reduce self-imposed heme toxicity. Analysis of diverse organisms indicates that HemX is widely conserved among heme-synthesizing bacteria, suggesting that HemX is a common factor involved in the regulation of GtrR abundance. Together, this work demonstrates that S. aureus regulates heme synthesis by modulating GtrR abundance in response to heme deficiency and through the activity of the broadly conserved HemX. IMPORTANCE Staphylococcus aureus is a leading cause of skin and soft tissue infections, endocarditis, bacteremia, and osteomyelitis, making it a critical health care concern. Development of new antimicrobials against S. aureus requires knowledge of the physiology that supports this organism’s pathogenesis. One component of staphylococcal physiology that contributes to growth and virulence is heme. Heme is a widely utilized cofactor that enables diverse chemical reactions across many enzyme families. S. aureus relies on many critical heme-dependent proteins and is sensitive to excess heme toxicity, suggesting S. aureus must maintain proper intracellular heme homeostasis. Because S. aureus provides heme for heme-dependent enzymes via synthesis from common precursors, we hypothesized that regulation of heme synthesis is one mechanism to maintain heme homeostasis. In this study, we identify that S. aureus posttranscriptionally regulates heme synthesis by restraining abundance of the first heme biosynthetic enzyme, GtrR, via heme and the broadly conserved membrane protein HemX.
format	article
author	Jacob E. Choby Caroline M. Grunenwald Arianna I. Celis Svetlana Y. Gerdes Jennifer L. DuBois Eric P. Skaar
author_facet	Jacob E. Choby Caroline M. Grunenwald Arianna I. Celis Svetlana Y. Gerdes Jennifer L. DuBois Eric P. Skaar
author_sort	Jacob E. Choby
title	<italic toggle="yes">Staphylococcus aureus</italic> HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis
title_short	<italic toggle="yes">Staphylococcus aureus</italic> HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis
title_full	<italic toggle="yes">Staphylococcus aureus</italic> HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis
title_fullStr	<italic toggle="yes">Staphylococcus aureus</italic> HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis
title_full_unstemmed	<italic toggle="yes">Staphylococcus aureus</italic> HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis
title_sort	<italic toggle="yes">staphylococcus aureus</italic> hemx modulates glutamyl-trna reductase abundance to regulate heme biosynthesis
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/405059706deb49fc97647c9d061a40c4
work_keys_str_mv	AT jacobechoby italictoggleyesstaphylococcusaureusitalichemxmodulatesglutamyltrnareductaseabundancetoregulatehemebiosynthesis AT carolinemgrunenwald italictoggleyesstaphylococcusaureusitalichemxmodulatesglutamyltrnareductaseabundancetoregulatehemebiosynthesis AT ariannaicelis italictoggleyesstaphylococcusaureusitalichemxmodulatesglutamyltrnareductaseabundancetoregulatehemebiosynthesis AT svetlanaygerdes italictoggleyesstaphylococcusaureusitalichemxmodulatesglutamyltrnareductaseabundancetoregulatehemebiosynthesis AT jenniferldubois italictoggleyesstaphylococcusaureusitalichemxmodulatesglutamyltrnareductaseabundancetoregulatehemebiosynthesis AT ericpskaar italictoggleyesstaphylococcusaureusitalichemxmodulatesglutamyltrnareductaseabundancetoregulatehemebiosynthesis
_version_	1718427270198067200

<italic toggle="yes">Staphylococcus aureus</italic> HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis

Ejemplares similares