Journal article

TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNF alpha

James E Vince, Diep Chau, Bernard Callus, W Wei-Lynn Wong, Christine J Hawkins, Pascal Schneider, Mark McKinlay, Christopher A Benetatos, Stephen M Condon, Srinivas K Chunduru, George Yeoh, Robert Brink, David L Vaux, John Silke

The Journal of Cell Biology | ROCKEFELLER UNIV PRESS | Published : 2008


Synthetic inhibitor of apoptosis (IAP) antagonists induce degradation of IAP proteins such as cellular IAP1 (cIAP1), activate nuclear factor kappaB (NF-kappaB) signaling, and sensitize cells to tumor necrosis factor alpha (TNFalpha). The physiological relevance of these discoveries to cIAP1 function remains undetermined. We show that upon ligand binding, the TNF superfamily receptor FN14 recruits a cIAP1-Tnf receptor-associated factor 2 (TRAF2) complex. Unlike IAP antagonists that cause rapid proteasomal degradation of cIAP1, signaling by FN14 promotes the lysosomal degradation of cIAP1-TRAF2 in a cIAP1-dependent manner. TNF-like weak inducer of apoptosis (TWEAK)/FN14 signaling nevertheless ..

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