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

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 {Delta}Rv1075c 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.