Crosstalk between NF-kappaB-activating and apoptosis-inducing proteins of the TNF-receptor complex.

The cytokine tumor necrosis factor (TNF) elicits a wide range of biological responses, including inflammation, cell proliferation, differentiation, and apoptosis. Although the molecular mechanisms of TNF signaling have been largely elucidated, the principle that regulates the balance of life and death is still unknown. This review will focus on the crosstalk that exists between proteins of the TNF receptor (TNF-R) signalosome, and which are involved in the initiation of nuclear factor kappa B (NF-kappaB) activation or apoptosis. At least four different mechanisms of regulation can be distinguished: (i) NF-kappaB-mediated induction of proteins of the TNF-R complex; (ii) NF-kappaB-independent protection against apoptosis by the TNF-R-associating factor 2 (TRAF2)-mediated recruitment of antiapoptotic proteins; (iii) dual activation of apoptosis and NF-kappaB by a single molecule; and (iv) amplification of the death signal by proteolytic inactivation of signaling proteins that are involved in NF-kappaB activation or cell survival.