The adapter protein tumor necrosis factor receptor (TNFR)1–associated death domain (TRADD) plays an essential role in recruiting signaling molecules to the TNFRI receptor complex at the cell membrane. Here we show that TRADD contains a nuclear export and import sequence that allow shuttling between the nucleus and the cytoplasm. In the absence of export, TRADD is found within nuclear structures that are associated with promyelocytic leukemia protein (PML) nuclear bodies. In these structures, the TRADD death domain (TRADD-DD) can activate an apoptosis pathway that is mechanistically distinct from its action at the membrane-bound TNFR1 complex. Apoptosis by nuclear TRADD-DD is promyelocytic leukemia protein dependent, involves p53, and is inhibited by Bcl-xL but not by caspase inhibitors or dominant negative FADD (FADD-DN). Conversely, apoptosis induced by TRADD in the cytoplasm is resistant to Bcl-xL, but sensitive to caspase inhibitors and FADD-DN. These data indicate that nucleocytoplasmic shuttling of TRADD leads to the activation of distinct apoptosis mechanisms that connect the death receptor apparatus to nuclear events.
Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms
Abbreviations used in this paper: AA, amino acid(s); CARD, caspase recruitment domain; CRM, chromosomal region maintenance protein; DAPK, death-associated protein kinase; DD, death domain; DED, death effector domain; FADD, Fas-associated DD protein; DISC, death-inducing signaling complex; FADD-DN, dominant negative FADD; GFP, green fluorescent protein; HIPK, homeodomain-interacting protein kinase; IAP, inhibitor of apoptosis protein; LMB, leptomycin B; NES, nuclear export sequence; MEF, mouse embryo fibroblast; NLS, nuclear localization signal; PML, promyelocytic leukemia protein; RIP, receptor-interacting protein; TNF, tumor necrosis factor; TNFR, TNF receptor; TRADD, TNFR1-associated DD protein; TRADD-DD, TRADD death domain; YFP, yellow fluorescent protein.
Michael Morgan, Jacqueline Thorburn, Pier Paolo Pandolfi, Andrew Thorburn; Nuclear and cytoplasmic shuttling of TRADD induces apoptosis via different mechanisms . J Cell Biol 10 June 2002; 157 (6): 975–984. doi: https://doi.org/10.1083/jcb.200204039
Download citation file:
Sign in
Client Account
Sign in via your Institution
Sign in via your InstitutionEmail alerts
Advertisement
Advertisement