Details

Autor(en) / Beteiligte

• Misra, Ravi S.
• Russell, Jennifer Q.
• Koenig, Andreas
• Hinshaw-Makepeace, Jennifer A.
• Wen, Renren
• Wang, Demin
• Huo, Hairong
• Littman, Dan R.
• Ferch, Uta
• Ruland, Jurgen
• Thome, Margot
• Budd, Ralph C.

Titel

Caspase-8 and c-FLIPL Associate in Lipid Rafts with NF-κB Adaptors during T Cell Activation

Ist Teil von

• The Journal of biological chemistry, 2007-07, Vol.282 (27), p.19365-19374

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2007

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-κB signaling and proliferation. It is unknown how caspase-8 is activated following T cell stimulation, and what is the caspase-8 substrate(s) that is necessary to initiate T cell cycling. We observe that following TCR ligation, a small portion of total cellular caspase-8 and c-FLIPL rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIPL at a known caspase-8 cleavage site. The active caspase·c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-κB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-κB regulators PKCθ, CARMA1, Bcl-10, and MALT1, which connect to the TCR. The lack of caspase-8 results in the absence of MALT1 and Bcl-10 in the active caspase complex. Consistent with this observation, inhibition of caspase activity attenuates NF-κB activation. The current findings define a link among TCR, caspases, and the NF-κB pathway that occurs in a sequestered lipid raft environment in T cells.