Apoptosis Adaptor Proteins

Apoptotic adaptor proteins play a critical role in regulating pro- and anti-apoptotic signaling pathways following activation of the death receptors. Adaptor proteins, such as FADD (Fas-associated death domain) and TRADD (TNF receptor-associated death domain), are recruited to ligand-activated, oligomerized death receptors to mediate apoptotic signaling pathways. Apoptotic adaptors associate with the cytoplasmic portion of the death receptors through a domain common to both known as the death domain (DD).

Following association with the ligand-bound receptor, the adaptor proteins recruit pro-caspase-8 or pro-caspase-10 by way of their death effector domains (DED) to form the DISC (death-inducing signaling complex). Formation of the DISC initiates a caspase signaling cascade that ultimately induces apoptosis. Other adaptor proteins mediate apoptotic signaling through distinct mechanisms. CRADD/RAIDD (caspase and RIP adaptor with a death domain), and PIDD (p53-induced protein with a death domain) are two adaptor proteins that associate with pro-caspase-2 to form the PIDDosome following DNA damage. Formation of this complex leads to the cleavage and activation of caspase-2.

DAXX (Fas death domain-associated-xx) and RIP1 (receptor interacting protein 1) are two additional adaptor proteins containing a death domain that are recruited to Fas or to TNF RI respectively, upon ligand binding. These two proteins are involved in mediating caspase-independent apoptotic signaling pathways. Like TNF RI and Fas, TRAIL receptors (TRAIL R1/DR4 or TRAIL R2/DR5) and DR3 also contain intracellular death domains and can induce apoptosis by way of adaptor-mediated caspase-8 or caspase-10 recruitment. In addition to promoting apoptosis, ligand binding to TNF RI (TNF-alpha), or DR3 (TWEAK) can cause the intracellular adaptor proteins to recruit TRAF-2 (TNF Receptor-associated factor 2). TRAF-2 signaling subsequently leads to the activation of NFkB which induces the expression of anti-apoptotic genes such as FLIP and Bcl-2.