M. tb co-opts the host Ub-system to manipulate and subdue host immunity. The surface immune receptors TLR2-TLR4 recognize M. tb or its associated molecular patterns to initiate downstream signaling events to generate innate immune responses against the pathogen. Downstream to TLRs, the adaptors TRAF6, TAB1-TAK1-binding protein 1, and TAB2-TAB3 sense Ub chains and affect the NFKB1 and MAP kinase signaling to produce proinflammatory cytokines TNF, IL12, IL6, and IL1B. The M. tb secreted effectors (e.g., Mpt53, PtpA, and Rv0222 co-opt the host Ub-system and affect the Ub-mediated activation of kinases MAP3K7 and TRAF6. It ultimately inhibits or activates the NFKB1 and MAPKs signaling and produces innate immune effector cytokines to dampen innate immunity against the pathogen. The host exploits one of the surface Ub-binding M. tb effectors [e.g., PE_PGRS29 (Rv1468c)] to start xenophagy against the pathogen and recruit receptor proteins SQSTM1, NBR1, CALCOCO2, and OPTN.