| First Author | Hong M | Year | 2024 |
| Journal | Cell Rep | Volume | 43 |
| Issue | 11 | Pages | 114966 |
| PubMed ID | 39520684 | Mgi Jnum | J:359835 |
| Mgi Id | MGI:7790335 | Doi | 10.1016/j.celrep.2024.114966 |
| Citation | Hong M, et al. (2024) Residue Y362 is crucial for FLIP(L) to impart catalytic activity to pro-caspase-8 to suppress necroptosis. Cell Rep 43(11):114966 |
| abstractText | The pro-form of caspase-8 prevents necroptosis by functioning in a proteolytically active complex with its catalytic-dead homolog, FLICE (FADD [Fas-associated death domain]-like interleukin 1beta-converting enzyme)-like inhibitory protein long-form (FLIP(L)). However, how FLIP(L) imparts caspase-8 the catalytic activity to suppress necroptosis remains elusive. Here, we show that the protease-like domain of FLIP(L) is essential for the activity of the caspase-8-FLIP(L) heterodimer in blocking necroptosis. While substitution of two amino acids whose difference may contribute to the pseudo-caspase property of FLIP(L) with the corresponding amino acids in caspase-8 does not restore the protease activity of FLIP(L), one of the amino acid replacements, tyrosine (Y) 362 to cysteine (C), is sufficient to completely abolish the activity of the caspase-8-FLIP(L) heterodimer in cleaving receptor-interacting protein 1 (RIP1), thus releasing the necroptosis blockade. Unconstrained necroptosis is observed in embryonic day (E)10.5-E11.5 embryos of FLIP(L)-Y362C knockin mice. Collectively, these results reveal that the protease-like domain of FLIP(L) has a special structure that imparts the pro-caspase-8-FLIP(L) heterodimer a unique catalytic activity toward RIP1 to prevent necroptosis. |
