ABSTRACT Mycobacterium tuberculosis(Mtb) lipoproteins are known to facilitate bacterial survival by manipulating the host immune responses. Here, we have characterized a novel Mtb lipoprotein LprE(LprE Mtb ), and demonstrated its role in mycobacterial survival. LprE Mtb acts by down-regulating the expression of cathelicidin, Cyp27B1, VDR and p38-MAPK via TLR-2 signaling pathway. Deletion of lprE Mtb resulted in induction of cathelicidin and decreased survival in the host. Interestingly, LprE Mtb was also found to inhibit autophagy mechanism to dampen host immune response. Episomal expression of LprE Mtb in non-pathogenic Mycobacterium smegmatis ( Msm ) increased bacillary persistence by down-regulating the expression of cathelicidin and autophagy, while deletion of LprE Mtb orthologue in Msm , had no effect on cathelicidin and autophagy expression. Moreover, LprE Mtb blocked phago-lysosome fusion by suppressing the expression of EEA1, Rab7 and LAMP-1 endosomal markers by down-regulating IL-12 and IL-22 cytokines. Our results indicate that LprE Mtb plays an important role in mycobacterial pathogenesis in the context of innate immunity.