Small proteins regulateSalmonellasurvival inside macrophages by controlling degradation of a magnesium transporter

Abstract

All cells require Mg2+to replicate and proliferate. The macrophage protein Slc11a1 is proposed to protect mice from invading microbes by causing Mg2+starvation in host tissues. However, the Mg2+transporter MgtB enables the facultative intracellular pathogenSalmonella entericaserovar Typhimurium to cause disease in mice harboring a functional Slc11a1 protein. Here, we report that, unexpectedly, theSalmonellasmall protein MgtR promotes MgtB degradation by the protease FtsH, which raises the question: How doesSalmonellapreserve MgtB to promote survival inside macrophages? We establish that theSalmonellasmall protein MgtU prevents MgtB proteolysis, even when MgtR is absent. Like MgtB, MgtU is necessary for survival inSlc11a1+/+macrophages, resistance to oxidative stress, and growth under Mg2+limitation conditions. TheSalmonellaMg2+transporter MgtA is not protected by MgtU despite sharing 50% amino acid identity with MgtB and being degraded in an MgtR- and FtsH-dependent manner. Surprisingly, themgtB,mgtR, andmgtUgenes are part of the same transcript, providing a singular example of transcript-specifying proteins that promote and hinder degradation of the same target. Our findings demonstrate that small proteins can confer pathogen survival inside macrophages by altering the abundance of related transporters, thereby furthering homeostasis.