Pi Hualiang, Patel Sarju J, Argüello José M, Helmann John D
Department of Microbiology, Cornell University, Ithaca, NY, 14853, USA.
Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA, 01609, USA.
Mol Microbiol. 2016 Jun;100(6):1066-79. doi: 10.1111/mmi.13368. Epub 2016 Apr 14.
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.
单核细胞增生李斯特菌FrvA（Lmo0641）对小鼠模型中的毒力至关重要，是枯草芽孢杆菌Fur和PerR调节的Fe（II）外排P1B4型ATP酶PfeT的直系同源物。此前，有人认为FrvA可抵御血红素毒性。在此，我们证明frvA突变体对铁中毒敏感，但对其他金属不敏感。frvA的表达受高铁诱导，且这种诱导需要Fur。FrvA在体外作为一种二价阳离子特异性ATP酶发挥作用，最易被亚铁强烈激活。当在枯草芽孢杆菌中表达时，FrvA可增强野生型和pfeT缺失菌株对铁的抗性。FrvA是一种高亲和力的Fe（II）输出蛋白，其诱导会导致枯草芽孢杆菌出现严重的铁限制，从而导致Fur和PerR调节基因的去阻遏。FrvA还可识别Co（II）和Zn（II）作为底物，并能补充枯草芽孢杆菌中这些阳离子内源性输出系统有缺陷的菌株。基于这些结果，我们得出结论，在李斯特菌感染期间，FrvA在Fe（II）的外排中起作用，而不是在血红素的外排中起作用。
