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Updated: Dec 13, 2025

Quantification of Cytosolic vs. Vacuolar Salmonella in Primary Macrophages by Differential Permeabilization
Published on: July 28, 2015
Small proteins regulate Salmonella survival inside macrophages by controlling degradation of a magnesium transporter
Jinki Yeom1,2,3, Yi Shao1, Eduardo A Groisman4,5
1Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536.
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 pathogen Salmonella enterica serovar Typhimurium to cause disease in mice harboring a functional Slc11a1 protein. Here, we report that, unexpectedly, the Salmonella small protein MgtR promotes MgtB degradation by the protease FtsH, which raises the question: How does Salmonella preserve MgtB to promote survival inside macrophages? We establish that the Salmonella small protein MgtU prevents MgtB proteolysis, even when MgtR is absent. Like MgtB, MgtU is necessary for survival in Slc11a1+/+ macrophages, resistance to oxidative stress, and growth under Mg2+ limitation conditions. The Salmonella Mg2+ 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, the mgtB, mgtR, and mgtU genes 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.
Insights
Salmonella uses small proteins to control magnesium transporter MgtB levels. MgtR promotes MgtB degradation, while MgtU prevents it, ensuring pathogen survival in macrophages.
Area of Science:
- Microbiology
- Molecular Biology
- Host-Pathogen Interactions
Background:
- Magnesium (Mg2+) is essential for cell replication and proliferation.
- The macrophage protein Slc11a1 limits microbial invasion by inducing Mg2+ starvation.
- Salmonella enterica serovar Typhimurium utilizes the Mg2+ transporter MgtB to cause disease in mice with functional Slc11a1.
Purpose of the Study:
- To investigate how Salmonella preserves MgtB for survival within macrophages.
- To identify the regulatory mechanisms controlling MgtB abundance in Salmonella.
Main Methods:
- Investigated the roles of small proteins MgtR and MgtU in regulating MgtB stability.
- Utilized genetic manipulation and proteolysis assays.
- Examined MgtB and MgtA transporter regulation.
Main Results:
- Salmonella small protein MgtR promotes MgtB degradation via the FtsH protease.
- Small protein MgtU prevents MgtB proteolysis, even in the absence of MgtR.
- MgtU is crucial for Salmonella survival in Slc11a1+/+ macrophages, oxidative stress resistance, and growth under Mg2+ limitation.
- MgtU does not protect the related MgtA transporter from degradation.
Conclusions:
- Small proteins MgtR and MgtU dynamically regulate the abundance of the MgtB Mg2+ transporter.
- This regulation is critical for Salmonella survival within host macrophages.
- The mgtB, mgtR, and mgtU genes form a single transcript, allowing coordinated control of MgtB levels.
- Small proteins can modulate transporter abundance to ensure pathogen homeostasis and survival.
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