Molecular Mechanisms of HipA-Mediated Multidrug Tolerance and Its Neutralization by HipB

Schumacher, Maria A.; Piro, Kevin M.; Xu, Weijun; Hansen, Sonja; Lewis, Kim; Brennan, Richard G.

doi:10.1126/science.1163806

Cited by 304 publications

(383 citation statements)

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“…The toxin components of the TA modules exert their effects in different ways by targeting essential cellular functions such as DNA replication, protein synthesis, cell division, peptidoglycan biosynthesis and ribosome assembly; however, RNA cleavage is the most prevalent mode of action [10][11][12][13][14][15][16] . These ribonucleases cleave RNA in either a ribosome-dependent (for example, RelE, HigB and YoeB) or ribosome-independent manner (for example, MazF, ToxN and VapC) 17,18 .…”

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confidence: 99%

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

et al. 2015

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Toxin-antitoxin (TA) systems are highly conserved in members of the Mycobacterium tuberculosis (Mtb) complex and have been proposed to play an important role in physiology and virulence. Nine of these TA systems belong to the mazEF family, encoding the intracellular MazF toxin and its antitoxin, MazE. By overexpressing each of the nine putative MazF homologues in Mycobacterium bovis BCG, here we show that Rv1102c (MazF3), Rv1991c (MazF6) and Rv2801c (MazF9) induce bacteriostasis. The construction of various single-, double-and triple-mutant Mtb strains reveals that these MazF ribonucleases contribute synergistically to the ability of Mtb to adapt to conditions such as oxidative stress, nutrient depletion and drug exposure. Moreover, guinea pigs infected with the triple-mutant strain exhibits significantly reduced bacterial loads and pathological damage in infected tissues in comparison with parental strain-infected guinea pigs. The present study highlights the importance of MazF ribonucleases in Mtb stress adaptation, drug tolerance and virulence.

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confidence: 99%

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

et al. 2015

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“…3B). This Lys is not commonly present in canonical kinases but is found in HipA and CtkA, two bacterial kinases that are remotely related to the Fam20 family (7,35,36).…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of the Golgi casein kinase

Xiao

Tagliabracci

Wen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The family with sequence similarity 20 (Fam20) kinases phosphorylate extracellular substrates and play important roles in biomineralization. Fam20C is the Golgi casein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs. Mutations in Fam20C cause Raine syndrome, an osteosclerotic bone dysplasia. Here we report the crystal structure of the Fam20C ortholog from Caenorhabditis elegans. The nucleotide-free and Mn/ ADP-bound structures unveil an atypical protein kinase-like fold and highlight residues critical for activity. The position of the regulatory αC helix and the lack of an activation loop indicate an architecture primed for efficient catalysis. Furthermore, several distinct elements, including the presence of disulfide bonds, suggest that the Fam20 family diverged early in the evolution of the protein kinase superfamily. Our results reinforce the structural diversity of protein kinases and have important implications for patients with disorders of biomineralization.P rotein phosphorylation is a fundamental mechanism that regulates numerous physiological processes (1, 2). Protein kinases have evolved to function as dynamic switches relaying signals in response to various stimuli by transferring a phosphate from ATP to target proteins (3-5). Most phosphoproteins are found within the cell, residing in the nuclei and cytosol; however, secreted proteins, including casein and other members of the secretory calciumbinding phosphoprotein family, are phosphorylated as well (6). We recently identified a family of kinases that reside in the secretory pathway and function to phosphorylate extracellular substrates (7,8). One member of this family, Fam20C (family with sequence similarity 20, member C), is the physiological casein kinase that phosphorylates multiple secreted proteins within a Ser-x-Glu/pSer motif (7, 9, 10). The importance of this discovery is underscored by the fact that some 75% of the phosphoproteins identified in human serum and cerebrospinal fluid contain phosphate within this motif (11-13). Furthermore, mutations in FAM20C cause Raine syndrome, a deadly osteosclerotic bone dysplasia characterized by generalized osteosclerosis, ectopic calcifications, and characteristic facial features (14-16). Most individuals with Raine syndrome die within a few weeks after birth; however, nonlethal cases with dental abnormalities and clinical features of hypophosphatemia have been reported (17,18). Loss of Fam20C in mice also results in severe bone and tooth anomalies, as well as hypophosphatemia (19)(20)(21).Two other closely related Fam20C paralogs, Fam20A and Fam20B, are present in humans (22). Fam20B is ubiquitously expressed and phosphorylates xylose within the tetrasaccharide linkage region of proteoglycans (23). This phosphorylation event may influence glycosaminoglycan biosynthesis (24). Genetic deletion of Fam20B in mice results in embryonic lethality at E13.5, and mutations in Danio rerio result in reduced cartilage matrix production and skeletal defects (19,25). The substra...

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“…However, how HipA mediates growth arrest is still unknown. It was found that HipA may phosphorylate elongation factor EF-tu (27), but HipA overexpression has been shown to arrest both translation and transcription (23), suggesting other targets for HipA.…”

Section: Discussionmentioning

confidence: 99%

“…These findings confirm that the hipBA TA module plays a key role in determining bacterial persistence. However, even though the structure of the HipBA complex is known (27) and growth arrest is shown to be due to HipA toxicity, any account of persistence must include an explanation of phenotypic variability: How does the coexistence of two distinct growth phenotypes within a genetically uniform population come about?…”

mentioning

confidence: 99%

Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence

Rotem

Loinger²,

Ronin³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

322

299

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In the face of antibiotics, bacterial populations avoid extinction by harboring a subpopulation of dormant cells that are largely drug insensitive. This phenomenon, termed "persistence," is a major obstacle for the treatment of a number of infectious diseases. The mechanism that generates both actively growing as well as dormant cells within a genetically identical population is unknown. We present a detailed study of the toxin-antitoxin module implicated in antibiotic persistence of Escherichia coli. We find that bacterial cells become dormant if the toxin level is higher than a threshold, and that the amount by which the threshold is exceeded determines the duration of dormancy. Fluctuations in toxin levels above and below the threshold result in coexistence of dormant and growing cells. We conclude that toxin-antitoxin modules in general represent a mixed network motif that can serve to produce a subpopulation of dormant cells and to supply a mechanism for regulating the frequency and duration of growth arrest. Toxinantitoxin modules thus provide a natural molecular design for implementing a bet-hedging strategy.single-cell | stochasticity | systems biology

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Molecular Mechanisms of HipA-Mediated Multidrug Tolerance and Its Neutralization by HipB

Cited by 304 publications

References 31 publications

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

Crystal structure of the Golgi casein kinase

Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence

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