C-terminal region of Rv1039c (PPE15) protein of Mycobacterium tuberculosis targets host mitochondria to induce macrophage apoptosis

Abstract

The genome of Mycobacterium tuberculosis (Mtb) encodes a unique family called Proline-Glutamate/Proline-Proline-Glutamate (PE/PPE) gene family, which is exclusive to pathogenic mycobacterium. Several proteins of this family are known to be virulent and utilize host signalling and cell death pathways leading to host immune response modulation, but functions of many of the PE/PPE proteins are yet to be identi ed. We studied the Rv1039c (PPE15) protein, which is known to be expressed at later stages of infection and known to be upregulated during dormancy. The C-terminal region of Rv1039c was found to be disordered, coiled and hydrophobic in nature and was observed to target the mitochondria of THP1 macrophages. Rv1039c with a deleted C-terminal reduced the mitochondrial perturbations, resulting in reduced depolarization of the mitochondrial membrane and the generation of mitochondrial superoxides. The C-terminal region of Rv1039c is responsible for activation of caspases 3, 7 and 9 along with enhanced expression of pro-apoptotic factors like Bax and Bim. Rv1039c also induced Cytochrome-C release from the mitochondria. Additionally, the C-terminal region of Rv1039c was observed to upregulate the expression levels of TLR4-NF-κB-TNF-α and antigen presenting HLA-DR molecules. These ndings revealed that the C-terminal region of Rv1039c is a molecular mimic of a proapoptotic host protein, inducing mitochondria-dependent macrophage apoptosis.