The hemX gene of the Bacillus subtilis hemAXCDBL operon encodes a membrane protein, negatively affecting the steady-state cellular concentration of HemA (glutamyl-tRNA reductase)

Schröder, Ingrid; Johansson, Per; Rutberg, Lars; Hederstedt, Lars

doi:10.1099/00221287-140-4-731

Cited by 20 publications

(12 citation statements)

References 32 publications

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“…Among both Gram-negative and Gram-positive bacteria, regulation of GtrR abundance is a common feature of heme synthesis regulation pathways ( 18 – 20 ). In the model organism Bacillus subtilis , which is also a member of the Firmicutes phylum, GtrR abundance is impacted by the membrane protein HemX through an unknown mechanism ( 18 , 21 ). While S. aureus is in the same Bacillales order as B. subtilis , S. aureus heme homeostasis is distinct because of its access to host heme and its resistance to heme toxicity mediated by HssRS.…”

Section: Resultsmentioning

confidence: 99%

Staphylococcus aureus HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis

Choby

Grunenwald

Celis

et al. 2018

mBio

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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.

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Section: Resultsmentioning

confidence: 99%

Staphylococcus aureus HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis

Choby

Grunenwald

Celis

et al. 2018

mBio

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“…Like Salmonella and E. coli, the Gram-positive bacterium Bacillus subtilis regulates levels of HemA. While a mechanistic explanation has not been described, the membrane protein HemX post-transcriptionally regulates HemA abundance in B. subtilis [38,65]. Homologs of B. subtilis HemX exist in multiple Gram-positive pathogens; however, the function of HemX and HemA regulation has yet to be detailed.…”

Section: Bacterial Heme Synthesismentioning

confidence: 99%

Heme Synthesis and Acquisition in Bacterial Pathogens

Choby

Skaar

2016

Journal of Molecular Biology

256

266

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Bacterial pathogens require the iron-containing cofactor heme to cause disease. Heme is essential to the function of hemoproteins, which are involved in energy generation by the electron transport chain, detoxification of host immune effectors, and other processes. During infection, bacterial pathogens must synthesize heme or acquire heme from the host; however, host heme is sequestered in high-affinity hemoproteins. Pathogens have evolved elaborate strategies to acquire heme from host sources, particularly hemoglobin, and both heme acquisition and synthesis are important for pathogenesis. Paradoxically, excess heme is toxic to bacteria and pathogens must rely on heme detoxification strategies. Heme is a key nutrient in the struggle for survival between host and pathogen, and its study has offered significant insight into the molecular mechanisms of bacterial pathogenesis.

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“…Uroporphorphyrin-III C-methyltransferase (HemX) is a single spanning inner membrane protein that regulates the activity of NAD(P)H:glutamyl-tRNA reductase (HemA) in the tetrapyrrole biosynthesis pathway (41). HemX (43 kDa) was identified in a 208-kDa complex in the BN gel ( Fig.…”

Section: Protein Complexes In the Inner Membranementioning

confidence: 99%

Protein Complexes of the Escherichia coli Cell Envelope

Stenberg

Chovanec

Maslen

et al. 2005

Journal of Biological Chemistry

191

215

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Protein complexes are an intrinsic aspect of life in the membrane. Knowing which proteins are assembled in these complexes is therefore essential to understanding protein function(s). Unfortunately, recent high throughput protein interaction studies have failed to deliver any significant information on proteins embedded in the membrane, and many membrane protein complexes remain ill defined. In this study, we have optimized the blue native-PAGE technique for the study of membrane protein complexes in the inner and outer membranes of Escherichia coli. In combination with second dimension SDS-PAGE and mass spectrometry, we have been able to identify 43 distinct protein complexes. In addition to a number of well characterized complexes, we have identified known and orphan proteins in novel oligomeric states. For two orphan proteins, YhcB and YjdB, our findings enable a tentative functional assignment. We propose that YhcB is a hitherto unidentified additional subunit of the cytochrome bd oxidase and that YjdB, which co-localizes with the ZipA protein, is involved in cell division. Our reference two-dimensional blue native-SDS-polyacrylamide gels will facilitate future studies of the assembly and composition of E. coli membrane protein complexes during different growth conditions and in different mutant backgrounds.It has been suggested that nearly all biochemical processes are performed by protein complexes (1). This is particularly true in cellular membranes, where many well characterized proteins assemble into complexes that carry out important tasks in energy generation, protein trafficking, and small molecule transport. Many uncharacterized proteins ("orphans") are also predicted to be localized in cell membranes (2, 3), and it is probable that they also often assemble into complexes. Identifying the interacting partners of these proteins is critical to understanding their function.Unfortunately, our knowledge of protein complexes in cellular membranes is poor, because membrane proteins are incompatible with commonly used protein interaction assays. High throughput studies on model systems (4 -11) have therefore consistently disregarded membrane proteins (12). Although genetic tools specific for membrane protein interactions have been developed (13-15), they have not yet been pursued past proof of principle.A related and elusive aspect of membrane biology pertains to how proteins are assembled into complexes following their insertion into the membrane. Although some folding chaperones have been identified for model substrates, the ubiquity of their roles is not known, and little is known about the assembly process. Robust and effective experimental assays are required to tackle the question of membrane protein assembly.Blue native (BN) 3 -PAGE (16, 17) offers an attractive proteomic solution for the analysis of membrane protein complexes. It has been successfully applied to respiratory complexes in mitochondria and Paracoccus denitrificans (18 -24) and photosynthetic complexes of chloroplasts and Synechocystis ...

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The hemX gene of the Bacillus subtilis hemAXCDBL operon encodes a membrane protein, negatively affecting the steady-state cellular concentration of HemA (glutamyl-tRNA reductase)

Cited by 20 publications

References 32 publications

Staphylococcus aureus HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis

Staphylococcus aureus HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis

Heme Synthesis and Acquisition in Bacterial Pathogens

Protein Complexes of the Escherichia coli Cell Envelope

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