The Listeria monocytogenes Fur‐regulated virulence protein FrvA is an Fe(II) efflux P_1B4‐type ATPase

Abstract

Listeria monocytogenes FrvA (Lmo0641) is critical for virulence in the mouse model and is an ortholog of the Bacillus subtilis Fur- and PerR-regulated Fe(II) efflux P1B4-type ATPase PfeT. Previously, FrvA was suggested to protect against heme toxicity. Here, we demonstrate that an frvA mutant is sensitive to iron intoxication, but not to other metals. Expression of frvA is induced by high iron and this induction requires Fur. FrvA functions in vitro as a divalent cation specific ATPase most strongly activated by ferrous iron. When expressed in B. subtilis, FrvA increases resistance to iron both in wild-type and in a pfeT null strain. FrvA is a high affinity Fe(II) exporter and its induction imposes severe iron limitation in B. subtilis resulting in derepression of both Fur- and PerR-regulated genes. FrvA also recognizes Co(II) and Zn(II) as substrates and can complement B. subtilis strains defective in the endogenous export systems for these cations. Building on these results, we conclude that FrvA functions in the efflux of Fe(II), and not heme, during listerial infection.

Iron Efflux by PmtA Is Critical for Oxidative Stress Resistance and Contributes Significantly to Group A Streptococcus Virulence

“…The orthologs of PmtA in B. subtilis and L. monocytogenes are controlled by both PerR and the regulator of iron homeostasis, Fur (ferric uptake regulator) (13,37). Importantly, there is evidence to suggest that Fur may activate the expression of pfeT and frvA in response to excess iron, which is consistent with a primary role for PfeT and FrvA in protection against Fe toxicity (13, 37).…”

“…In WT GAS, any role for PmtA in Zn(II) detoxification is likely masked by the presence of Zn(II)-inducible efflux systems. Consistent with this, the contribution of FrvA to Zn(II) resistance became apparent only in strains lacking the endogenous Zn(II) efflux transporters (13). Bacterial pathogens counter oxidative stress by replacing ROS-sensitive iron at the catalytic centers of metalloenzymes with unreactive, noncognate metals such as Zn(II) and Mn(II) (17).…”

“…In contrast with copper and zinc, relatively little is known regarding the possible role of iron toxicity as a host nutritional immune mechanism during infection. Recent data, however, suggest that iron efflux contributes to microbial pathogenesis in some systems, although it is presently unclear whether this is a stress actively imposed by the host (13).…”

The PerR-Regulated P 1B-4 -Type ATPase (PmtA) Acts as a Ferrous Iron Efflux Pump in Streptococcus pyogenes

“…Here, we demonstrate that PmtA is a PerR-regulated GAS P 1B-4 P-type ATPase that contributes to resistance to oxidative stress through the removal of prooxidant Fe(II) from the intracellular environment. Our observations coincide with the P 1B-4 P-type ATPases PfeT of B. subtilis (18) and FrvA of L. monocytogenes (19), both of which are also Fe(II) efflux pumps regulated by the Fur family of regulators. The likely role of PmtA as an Fe(II) exporter is further supported by the observation that the pmtA deletion mutant accumulated higher levels of Fe(II) than did the WT strain under both normal and Fe(II) stress conditions.…”

“…The possibility that Fe ions might also be effluxed from the bacterial cell during peroxide stress has not been widely investigated. Recently, however, two P-type ATPases that mediate bacterial Fe efflux, PfeT of Bacillus subtilis, which is regulated by Fur and PerR (18), and FrvA of Listeria monocytogenes, which is regulated by Fur (19), have been described.…”