Mycobacterium tuberculosis manipulates host inflammation and lipid metabolism through the SET1-interacting protein Rv1075c

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ABSTRACT A growing body of literature supports a critical role for nucleomodulins, proteins that traffic to host cell nuclei and manipulate nuclear processes, in intracellular bacterial pathogenesis. Here, we identify the Mycobacterium tuberculosis (Mtb) secreted protein Rv1075c as a nucleomodulin that targets a histone modifying protein complex in macrophages. We report that ΔRv1075c Mtb infection elicits a blunted transcriptional response in inflammatory and lipid metabolism pathways and fails to induce foamy macrophage formation in the lungs of infected mice. Using an unbiased mass-spectrometry based approach, we found that Rv1075c interacts with components of the H3K4me3-depositing SET1 histone methyltransferase complex, and that this interaction is required for Rv1075c nuclear localization. Consistent with Rv1075c inhibiting SET1 activity, SET1 deficiency results in hyperinduction of inflammatory genes in activated macrophages. Together, these findings reveal a mechanism by which Mtb engages host chromatin machinery and support a model whereby Rv1075c exploits the SET1 complex to promote a host environment conducive to mycobacterial persistence. IMPORTANCE Tuberculosis is caused by Mycobacterium tuberculosis (Mtb), a remarkably adaptable bacterial pathogen that can survive inside the very immune cells that are supposed to destroy it. To survive, Mtb has evolved ways to interfere with the body’s natural defenses and create conditions that help it persist. Understanding how the bacterium accomplishes this is critical for developing better treatments for TB. In this study, we found that Mtb produces a protein called Rv1075c that travels to the nucleus of infected cells, where it interacts with chromatin remodeling proteins that regulate gene expression. By altering how these genes are controlled, Rv1075c increases the activity of genes involved in inflammation and lipid metabolism, creating a pro-bacterial environment. These findings reveal a previously unknown way that Mtb hijacks host cell gene expression to promote infection, providing new insight into how TB causes disease and suggesting potential targets for future therapies.

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