UCSF

During infection, Mycobacterium tuberculosis uses the ESX-1 secretion system to deliver bacterial proteins into host cells. Although this system is an important virulence determinant, its regulation is not well understood. Here we show that the protease MycP1 regulates ESX-1 and is required for virulence in mice. ESX-1 secretion is abolished in the absence of MycP1 but, unexpectedly, inhibition of MycP1 protease activity leads to enhanced secretion of ESX-1 substrates. During macrophage infection, increased ESX-1 secretion leads to hyper-activation of innate signaling pathways, including the cytosolic surveillance response. We show that MycP1 directly cleaves EspB, which is an ESX-1 substrate that is required for secretion. We hypothesize that MycP1 protein is required for ESX-1 machine assembly but that its protease activity negatively regulates secretion by cleaving EspB. As the key ESX-1 substrates ESAT-6 and CFP-10 are highly immunogenic, regulation of their secretion by MycP1 may be essential for successful establishment of M. tuberculosis infection.