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Review
. 2015 Apr:24:1-6.
doi: 10.1016/j.mib.2014.12.004. Epub 2015 Jan 10.

Oxidative stress protection by polyphosphate--new roles for an old player

Michael J Gray  1 , Ursula Jakob  2
Affiliations
Review

Oxidative stress protection by polyphosphate--new roles for an old player

Michael J Gray et al. Curr Opin Microbiol. 2015 Apr.

Abstract

Inorganic polyphosphate is a universally conserved biopolymer whose association with oxidative stress resistance has been documented in many species, but whose mode of action has been poorly understood. Here we review the recent discovery that polyphosphate functions as a protein-protective chaperone, examine the mechanisms by which polyphosphate-metal ion interactions reduce oxidative stress, and summarize polyphosphate's roles in regulating general stress response pathways. Given the simple chemical structure and ancient pedigree of polyphosphate, these diverse mechanisms are likely to be broadly relevant in many organisms, from bacteria to mammalian cells.

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Figures

Figure 1
Figure 1
Polyphosphate acts as a chaperone to prevent aggregation of oxidatively damaged proteins. Proteins damaged by oxidation, especially by the strong oxidant HOCl, are prone to cytotoxic aggregation. PolyP, generated from ATP under oxidative stress conditions, forms stable complexes with unfolding proteins, keeping them soluble and competent to be refolded. Upon relief of stress, polyP can be reconverted to ATP, which can then be used by ATP-dependent chaperones (e.g. DnaK, DnaJ, and GrpE) to refold polyP-protected proteins. Modified with permission from [8]. Abbreviations: HOCl, hypochlorous acid; ATP, adenosine triphosphate; polyP, inorganic polyphosphate.
Figure 2
Figure 2
Polyphosphate-metal complexes play multiple roles in oxidative stress resistance. (A) MnHPO4, likely to be generated by PPX digestion of manganese-polyP complexes, catalyzes dismutation of superoxide to O2 and H2O2. (B) Mn2+ ions in complex with polyP can non-catalytically quench superoxide, yielding Mn3+ and H2O. (C) Complex formation between polyP and redox active metals (e.g. Fe2+, Cu2+) reduces the yield of hydroxyl radicals by slowing regeneration of the Fenton-reactive Fe2+. (D) PolyP facilitates export of Cu2+ via a process requiring PPX and the metal-phosphate symporters PitA and PitB. Abbreviations: PPX, exopolyphosphatase; H2O2, hydrogen peroxide; OH•, hydroxyl radical; O2−, superoxide.
Figure 3
Figure 3
Polyphosphate regulates general stress response networks. (A) In E. coli, the stress alarmone (p)ppGpp inhibits PPX, stimulating accumulation of polyP. PolyP activates Lon protease, which then degrades the antitoxin components of type II toxin-antitoxin systems. Accumulation of free toxin reduces growth rate and leads to an increase in formation of broadly stress-resistant persister cells. (B) In E. coli, the general stress response regulon controlled by the sigma factor σ38 includes genes encoding PPK, catalase, and superoxide dismutase. PolyP activates expression of the rpoS gene encoding σ38. (C) In M. tuberculosis, polyP is required for MprAB-dependent expression of the stress response sigma factor σE, which controls polyP and (p)ppGpp biosynthesis and is required for stress resistance, virulence, and persistence in macrophages. Oxidative stress (e.g. H2O2) leads to activation of σE by inactivating the σE anti-sigma factor RseA. Abbreviations: ATP, adenosine triphosphate; (p)ppGpp, guanosine penta-or tetra-phosphate; PPK and PPK1, polyphosphate kinase; PPX, exopolyphosphatase; H2O2, hydrogen peroxide; O2−, superoxide.
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