A role for tetrahydrofolates in the metabolism of iron-sulfur clusters in all domains of life

Waller, Jeffrey C.; Alvarez, Sophie; Naponelli, Valeria; Lara‐Núñez, Aurora; Blaby, Ian K.; Silva, Vanessa da; Ziemak, Michael J.; Vickers, Tim J.; Beverley, Stephen M.; Edison, Arthur S.; Rocca, James R.; Gregory, Jesse F.; Crécy‐Lagard, Valérie de; Hanson, Andrew D.

doi:10.1073/pnas.0911586107

Cited by 77 publications

(121 citation statements)

References 38 publications

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“…YgfZ is a folate-binding protein (Teplyakov et al, 2004;Waller et al, 2010), but exogenous folate did not enhance CNF1 secretion (data not shown). YgfZ belongs to the COG0354 group, which was suggested to have a conserved, folate-dependent function in the activity of certain Fe-S cluster enzymes (Waller et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…YgfZ belongs to the COG0354 group, which was suggested to have a conserved, folate-dependent function in the activity of certain Fe-S cluster enzymes (Waller et al, 2010). Previously, we pCTC-YgfZ is the expression plasmid of FLAG-tagged YgfZ; pCTS-BAP represents pFLAG-CTS-BAP (Sigma), which is a 6735 bp E. coli plasmid used for efficient and controlled periplasmic expression of C-terminal FLAG-BAP fusion protein.…”

Section: Discussionmentioning

confidence: 99%

“…YgfZ belongs to the COG0354 group, which was suggested to have a conserved, folate-dependent function in the activity of certain Fe-S cluster enzymes (Waller et al, 2010). Previously, we identified that ferredoxin (Fe-S assembly protein) is involved in CNF1 secretion across the bacterial inner membrane (Yu & Kim, 2010), and comparative genomics studies suggest that COG0354 genes cluster with genes encoding Fe-S enzymes or related proteins (Waller et al, 2010). These findings suggest that Fe-S protein may be involved with YfgZ in the CNF1 secretion system.…”

Section: Discussionmentioning

confidence: 99%

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YgfZ contributes to secretion of cytotoxic necrotizing factor 1 into outer-membrane vesicles in Escherichia coli

Kim

2012

Microbiology

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Cytotoxic necrotizing factor 1 (CNF1), a Rho GTPase-activating bacterial toxin, has been shown to contribute to invasion by meningitis-causing Escherichia coli K1 of human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier. However, CNF1 is a cytosolic protein and it remains unclear how its secretion occurs, contributing to E. coli invasion of HBMEC. To investigate the genetic requirement for CNF1 secretion in E. coli K1 strain RS218, we performed mini-Tn5 in vitro mutagenesis and constructed a transposon mutant library of strain NBC, in which b-lactamase was fused to the C-terminus of CNF1 in the chromosome of strain RS218. We identified a transposon mutant (NBC-1E6) that exhibited reduced b-lactamase activity in its culture supernatant and had the transposon inserted into the ygfZ gene. When ygfZ was deleted from the genome of strain RS218 (DygfZ), the translocation of CNF1 into HBMEC was impaired. Subcellular localization analysis of CNF1 demonstrated that YgfZ, a periplasmic protein, contributes to secretion of CNF1 into outer-membrane vesicles (OMVs). The DygfZ mutant was significantly defective in invasion of HBMEC compared to the parent E. coli K1 strain. The defects of the DygfZ mutant in CNF1 secretion into OMVs and translocation into HBMEC as well as invasion of HBMEC were abrogated by complementation with ygfZ. Taken together, our findings demonstrate that YgfZ contributes to CNF1 secretion into OMVs in meningitis-causing E. coli K1. INTRODUCTIONCNF1, the paradigm of the Rho GTPase-activating bacterial toxins (Boquet, 2001;Knust & Schmidt, 2010;Lemonnier et al., 2007), is frequently associated with uropathogenic and meningitis-causing Escherichia coli strains (Khan et al., 2002;Landraud, et al., 2000). CNF1 activates Rho GTPases by deamidation of glutamine 63, converting it into glutamic acid, thus inhibiting GTPhydrolysing activity, resulting in constitutive activation of Rho GTPase. CNF1 has been shown to contribute to polymerization of F-actin, increased formation of stress fibres and phagocytosis (Caprioli et al., 1983;Falzano et al., 1993;Flatau et al., 1997;Schmidt et al., 1997; VouretCraviari et al., 1999). CNF1-like toxins have also been found in other bacteria, including the dermonecrotic toxin of Bordetella spp. and the CNFc from Yersinia pseudotuberculosis (Knust & Schmidt, 2010;Kume et al., 1986;Lockman et al., 2002).We have shown that CNF1 contributes to invasion by E. coli K1 of human brain microvascular endothelial cells (HBMEC) and penetration into the brain via the interaction with its receptor, 37 laminin receptor precursor (37LRP)/67 laminin receptor (67LR) (Chung et al., 2003;Khan et al., 2002;Kim et al., 2005). CNF1 is a cytoplasmic protein and its secretion is, therefore, a strategy utilized by meningitis-causing E. coli K1 to invade the blood-brain barrier (Khan et al., 2002;Kim, 2003Kim, , 2008. However, it remains incompletely understood how CNF1 secretion occurs. No typical signal peptide is found in the CNF1 sequence. Recent studies have ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…YgfZ belongs to the COG0354 group, which was suggested to have a conserved, folate-dependent function in the activity of certain Fe-S cluster enzymes (Waller et al, 2010). Previously, we identified that ferredoxin (Fe-S assembly protein) is involved in CNF1 secretion across the bacterial inner membrane (Yu & Kim, 2010), and comparative genomics studies suggest that COG0354 genes cluster with genes encoding Fe-S enzymes or related proteins (Waller et al, 2010). These findings suggest that Fe-S protein may be involved with YfgZ in the CNF1 secretion system.…”

Section: Discussionmentioning

confidence: 99%

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YgfZ contributes to secretion of cytotoxic necrotizing factor 1 into outer-membrane vesicles in Escherichia coli

Kim

2012

Microbiology

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“…Folates are particularly important during periods of rapid cell division and growth (Blakley, 1969, Green et al, 1996. Redrawn from (Waller et al, 2010). (C) Scanning spectrophotometric analysis of MTHFS reaction, which converts 5-CHO-H 4 PteGlu (Abs, 285nm) to 5,10-CH + -H 4 PteGlu (Abs, 360 nm), catalyzed by the M. tuberculosis MTHFS homolog, Rv0992c, a novel determinant of antifolate resistance.…”

Section: Antifolatesmentioning

confidence: 99%

Potentiation of Available Antibiotics by Targeting Resistance – An Emerging Trend in Tuberculosis Drug Development

Wolff¹,

Sherman²,

Nguyen³

2011

Drug Development - A Case Study Based Insight Into Modern Strategies

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“…CyaY is hypothesized to be an Fe donor for [Fe-S] cluster biosynthesis (1,49). The function of YgfZ remains unknown (51).…”

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confidence: 99%

Decreased Transport Restores Growth of a Salmonella enterica apbC Mutant on Tricarballylate

2012

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Mutants of Iron and sulfur are essential to almost all bacteria, and cofactors containing these elements ([Fe-S] clusters) are nearly ubiquitous. Evolution has harnessed the flexible biochemical and biophysical properties of these cofactors for a variety of cellular functions, including enzymatic reactions, electron transfer, DNA metabolism, and environmental sensing (reviewed in references 8 and 27).Three systems for [Fe-S] cluster biosynthesis have been described in bacteria. Work with Azotobacter vinelandii led to the discovery of the nif (nitrogen fixation) (55) and isc (iron-sulfur cluster) (54) [Fe-S] cluster biosynthetic operons. A third system, encoded by the suf (sulfur utilization factor) operon, was discovered in Escherichia coli (47). The genome of Salmonella enterica serovar Typhimurium encodes both the iscSUA-hscAB-fdx-orf3 and sufABCDSE operons (36,47).Both bioinformatics and in vivo genetic approaches have identified several loci outside the isc, suf, and nif operons that impact [Fe-S] cluster metabolism. The apbC, rseC, and apbE loci were discovered in Salmonella enterica by using sensitive genetic screens that exploited phenotypes described for strains lacking isc operon functions (6,7,38,(44)(45)(46). ApbC is a 40-kDa cytoplasmic protein that can bind and rapidly transfer [Fe-S] clusters to a target protein (15) and hydrolyze ATP (16,44). Both of these activities are necessary for in vivo function (16). ApbC is a representative member of an ancient family of [Fe-S] cluster biosynthetic proteins that evolved before the divergence of the Archaea and Eucarya (13). To our knowledge, all organisms that have sequenced genomes and are known to metabolize iron encode a copy of an apbC homologue. In contrast, the functions of the rseC and apbE gene products remain unknown.The erpA, nfuA, cyaY, and ygfZ genes were identified in bacteria by using bioinformatic approaches, and subsequent physiological studies found that these gene products function in 4,35,37,49). The NfuA and ErpA proteins show sequence similarity to the proposed [Fe-S] cluster-trafficking pro-

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A role for tetrahydrofolates in the metabolism of iron-sulfur clusters in all domains of life

Cited by 77 publications

References 38 publications

YgfZ contributes to secretion of cytotoxic necrotizing factor 1 into outer-membrane vesicles in Escherichia coli

YgfZ contributes to secretion of cytotoxic necrotizing factor 1 into outer-membrane vesicles in Escherichia coli

Potentiation of Available Antibiotics by Targeting Resistance – An Emerging Trend in Tuberculosis Drug Development

Decreased Transport Restores Growth of a Salmonella enterica apbC Mutant on Tricarballylate

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