Figure 1.
TNF-Mediated Death and Survival Pathways
TNF-mediated death and survival pathways are activated following interaction with the TNFRs. The apoptotic pathway is activated through TNFR1 by forming the DISC, which activates caspase-8. Activated caspase-8 or −10 then activates the proapoptotic Bcl-2 family members, which leads to cell death by releasing cytochrome c from mitochondria and loss of MMP. The NF-κB-mediated survival pathway is activated by both TNFR1 and TNFR2. Association of TRAFs with these receptors activate signaling proteins like NIK (NF-κB inhibitor kinase) and MEKK1 (MAPK kinase 1), which activate the inhibitor of NF-κB (IkB) kinase (IKK) signalosome complex. IKK phosphorylates IkB, resulting in the degradation of the inhibitor. The free NF-κB than translocates to nucleus to induce the expression of inflammatory or antiapoptotic genes.
Figure 2.
Different Strategies for Inhibiting TNF by Pathogens
Pathogens have evolved diverse strategies to target almost every step of TNF biology. Virus-encoded proteins inhibit TNF-mediated responses by directly binding to TNF with secreted soluble decoy TNFR (vTNFRs) and vTNFBPs, downregulating the cellular death receptors, interacting with the TNFR-associated factors, blocking caspase activation, and regulating the apoptotic checkpoint function of mitochondria. Viruses also regulate the pathways leading to TNF-mediated activation of NF-κB. Bacteria and other pathogens can express proteins that regulate TNF-mediated responses by activating or inhibiting NF-κB at different levels of signaling that range from the death receptor to nuclear localization of NF-κB.
Table 1.
Viral Inhibition and Modulation of TNF
Table 2.
Modulation of TNF by Bacteria and Parasites