CFLAR Gene: CASP8 and FADD Like Apoptosis Regulator - Function, Mutations & Disease

The CFLAR gene encodes a protein that is a regulator of apoptosis (programmed cell death). It is a cytoplasmic protein similar to caspase-8 but lacks catalytic activity. It functions as an inhibitor of death receptor-induced apoptosis by competing with caspase-8 for binding to the death-inducing signaling complex (DISC). CFLAR also modulates necroptosis and NF-κB signaling. Alternative splicing generates several isoforms, with the long form (c-FLIPL) and short form (c-FLIPS) having distinct roles. Dysregulation of CFLAR is implicated in various cancers, autoimmune diseases, and viral infections.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Apoptosis - multiple species (KEGG hsa04215)

• TNF signaling pathway (KEGG hsa04668)

• NF-kappa B signaling pathway (KEGG hsa04064)

• Death Receptor Signaling (Reactome R-HSA-73887)

• Regulation of necroptosis (Reactome R-HSA-5213460)

The CFLAR protein (c-FLIP) is a 480-amino acid (long isoform) cytoplasmic protein that shares structural homology with caspase-8 but lacks proteolytic activity. It contains two death effector domains (DEDs) at the N-terminus and a caspase-like domain at the C-terminus. c-FLIP is recruited to the DISC via FADD, where it inhibits caspase-8 activation and prevents apoptosis. The short isoform (c-FLIPS) lacks the caspase-like domain and acts as a stronger inhibitor. Post-translational modifications include phosphorylation and ubiquitination, which regulate its stability and function. CFLAR also interacts with TRAF2 and RIPK1 to modulate NF-κB and necroptosis pathways.