TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1–TRAF2 complex to sensitize tumor cells to TNFα
- Vince, James E. Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, VIC 3086, Australia
- Chau, Diep Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, VIC 3086, Australia
- Callus, Bernard Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, VIC 3086, Australia
- Wong, W. Wei-Lynn Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, VIC 3086, Australia
- Hawkins, Christine J. Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, VIC 3086, Australia
- Schneider, Pascal Biochemistry Department, University of Lausanne, CH-1066 Epalinges, Switzerland
- McKinlay, Mark TetraLogic Pharmaceuticals, 365 Phoenixville Pike, Malvern, PA 19355
- Benetatos, Christopher A. TetraLogic Pharmaceuticals, 365 Phoenixville Pike, Malvern, PA 19355
- Condon, Stephen M. TetraLogic Pharmaceuticals, 365 Phoenixville Pike, Malvern, PA 19355
- Chunduru, Srinivas K. TetraLogic Pharmaceuticals, 365 Phoenixville Pike, Malvern, PA 19355
- Yeoh, George Department of Biochemistry, The University of Western Australia, Crawley, 6009, Australia
- Brink, Robert Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia
- Vaux, David L. Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, VIC 3086, Australia
- Silke, John Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, VIC 3086, Australia
- 2008-7-7
Published in:
- Journal of Cell Biology. - Rockefeller University Press. - 2008, vol. 182, no. 1, p. 171-184
English
Synthetic inhibitor of apoptosis (IAP) antagonists induce degradation of IAP proteins such as cellular IAP1 (cIAP1), activate nuclear factor κB (NF-κB) signaling, and sensitize cells to tumor necrosis factor α (TNFα). 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 promotes the same noncanonical NF-κB signaling elicited by IAP antagonists and, in sensitive cells, the same autocrine TNFα-induced death occurs. TWEAK-induced loss of the cIAP1–TRAF2 complex sensitizes immortalized and minimally passaged tumor cells to TNFα-induced death, whereas primary cells remain resistant. Conversely, cIAP1–TRAF2 complex overexpression limits FN14 signaling and protects tumor cells from TWEAK-induced TNFα sensitization. Lysosomal degradation of cIAP1–TRAF2 by TWEAK/FN14 therefore critically alters the balance of life/death signals emanating from TNF-R1 in immortalized cells.
- Language
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- English
- Open access status
- hybrid
- Identifiers
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- DOI 10.1083/jcb.200801010
- ISSN 1540-8140
- Persistent URL
- https://sonar.ch/global/documents/46453
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