c-FLIPS reduces activation of caspase and NF-κB pathways and decreases T cell survival

✍ Scribed by Jennifer Hinshaw-Makepeace; Gail Huston; Karen A. Fortner; Jennifer Q. Russell; Daniel Holoch; Susan Swain; Ralph C. Budd

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 317 KB
• Volume: 38
• Category: Article
• ISSN: 0014-2980
• DOI: 10.1002/eji.200636956

✦ Synopsis

Abstract

Effective stimulation of NF‐κB in T cells following TCR ligation requires the activity of caspase‐8. The active caspase‐8 complex includes the paracaspase, MALT1, and Bcl‐10, which connect to the NF‐κB pathway. It has been less clear what regulates the level of caspase‐8 activity during T cell activation. A likely candidate is cellular FLIP (c‐FLIP), an enzymatically inert caspase‐8 homologue. Two alternatively spliced forms of c‐FLIP exist, a long form (c‐FLIP~L~) and a short‐form (c‐FLIP~S~). The latter lacks the C‐terminal caspase‐like domain. c‐FLIP~L~ can heterodimerize with and activate caspase‐8 through an activation loop in the C terminus of c‐FLIP~L~. Here we show that, in contrast to c‐FLIP~L~, c‐FLIP~S~ inhibits activation of caspase‐8 in T cells, and consequently reduces recruitment of MALT1 and Bcl‐10 to the active caspase complex. This results in reduced activity of NF‐κB. Consequently, T cells from c‐FLIP~S~‐transgenic mice undergo more rapid cell death both spontaneously and after activation. The findings suggest that c‐FLIP~S~ functions to reduce the expansion of T cells during an immune response.