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bioRxiv · 10.64898/2026.06.04.730267

Inorganic sulfate transport by the Mycobacterium tuberculosis PE22/PPE36 complex

Tripathi, A.·Boradia, V.·Wu, A.·Dawkins, M.·Saleh, A.·Rhee, K. Y.·Grundner, C.
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Abstract

Mycobacterium tuberculosis (Mtb) encodes two multigene families with 169 members that are exclusive to mycobacteria, the pe and ppe genes. These genes have unusual sequences including low-complexity repeat regions, but their functions--and whether they share a common function--have long been unclear. Recently, several members of the pe/ppe family were shown to transport nutrients across the outer Mtb membrane, a role for which no other proteins have yet been identified. Whether nutrient transport is a family-wide function and the range of nutrients transported by the PE/PPEs remains unclear. Sulfur is an essential nutrient for Mtb physiology and pathogenesis. To test whether PE/PPE transporters contribute to sulfur acquisition, we analyzed the transcriptional response of Mtb to sulfate by RNA sequencing. The pe22/ppe36 genes were induced in sulfate-limiting conditions. Deletion of pe22/ppe36 impaired growth in low-sulfate media and reduced intracellular sulfate levels, effects that were reversed by heterologous expression of the Mycobacterium smegmatis porin MspA. The response of sulfur-responsive genes to sulfur was muted in the pe22/ppe36 deletion strain, and mass spectrometry showed lower sulfolipid and sulfur metabolite levels in the deletion strain. These findings identify PE22/PPE36 as a specific sulfate uptake system and supports the emerging idea of PE/PPE proteins as nutrient uptake systems across the Mtb outer membrane. Significance statementThe mechanism of nutrient transport across the porin-less mycobacterial outer membrane and the function of the large pe/ppe gene family have been longstanding questions in mycobacterial biology. This study shows that the Mycobacterium tuberculosis PE22/PPE36 complex serves as a selective conduit for inorganic sulfate. Deletion of this complex disrupts intracellular sulfur homeostasis and triggers a metabolic seesaw that depletes cell-surface sulfolipids. Our findings expand the PE/PPE transport paradigm and suggest a direct link between nutrient acquisition and TB transmission.

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Tripathi, A., Boradia, V., Wu, A., Dawkins, M., Saleh, A., Rhee, K. Y., Grundner, C.. 2026-06-05. Inorganic sulfate transport by the Mycobacterium tuberculosis PE22/PPE36 complex. https://doi.org/10.64898/2026.06.04.730267

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