The Association of TRAF‐2 with the Short form of Cellular FLICE‐like Inhibitory protein prevents TNFR1‐ mediated apoptosis

• Published in: The FASEB journal 2006-03, Vol.20 (5), p.LB72-LB72
• Main Authors: kim, youngyoul, Kim, dongjun, Park, sungjoon, Oh, kyungsoo, Kimm, kyuchan, park, Chan
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.20.5.LB72-b

The induction of apoptosis by TNF is thought to proceed via the recruitment of both the FADD adaptor and caspase‐8 to its receptor complex. However, the surface expression of TNF does not necessarily render cells susceptible to TNF‐induced death signals. This indicates that inhibitors of these apoptosis‐signaling pathways must exist. The full characterization of the inhibitor of apoptosis, c‐FLIP (cellular FLICE‐inhibitory protein), and the mechanisms by which each of its two splicing variants suppresses the apoptotic death signal remain to be elucidated. We now report in our current study that the short form of c‐FLIP (c‐FLIPS) is a more efficient inhibitor of TNF‐receptor 1 (TNFR1) mediated apoptosis signaling than the long form of the protein (c‐FLIPL). The initial plasma membrane bound complex consists of TNFR1, the adaptor TRADD, RIP1 kinase and TRAF‐2, and rapidly induces the activation of NF‐κB. When NF‐κB is activated by TNFR1, c‐FLIPS is activated by c‐jun‐N‐terminal Kinase (JNK) via TRAF‐2 in an autocrine regulatory loop. Therefore, the induction of c‐FLIPL in response to TNFα is achieved in a more delayed manner than that of c‐FLIPS. Our present study therefore suggests that alternative splicing variants of c‐FLIP perform different roles in spite of fact that they operate in the same pathway.