cFLIP

cFLIP, or cellular FLICE-like inhibitory protein, is a regulator of death receptor–mediated programmed cell death in humans. It is encoded by the CFLAR gene and functions primarily at the death-inducing signaling complex (DISC) to inhibit the activation of caspase-8, thereby blocking apoptosis in response to death receptors such as Fas and TRAIL receptors. cFLIP also participates in modulating other signaling pathways, including inflammatory and survival signals, depending on cellular context.

Protein structure and isoforms: cFLIP proteins contain two N-terminal death effector domains (DEDs) that enable binding to FADD and procaspase-8, followed by a C-terminal region that resembles a caspase-like domain but is catalytically inactive. The CFLAR gene produces several isoforms through alternative splicing, the most studied being cFLIP_L (long) and cFLIP_S (short); a less common variant, cFLIP_R, also exists. The long isoform retains a pseudo-caspase domain, whereas the short and related isoforms lack functional proteolytic activity.

Function and mechanisms: At the DISC, cFLIP variants compete with procaspase-8 for FADD binding, inhibiting caspase-8 activation and apoptosis. cFLIP_L can form heterodimers with caspase-8 that may allow limited caspase-8 activity in certain conditions, contributing to a nuanced balance between survival and death signals. Beyond apoptosis, cFLIP influences necroptosis by regulating caspase-8–mediated cleavage events, and it can affect NF-κB–driven inflammatory and survival pathways. It also plays roles in autophagy and immune cell signaling in specific contexts.

Regulation and clinical relevance: CFLAR expression is controlled by transcriptional and post-translational mechanisms, including NF-κB signaling and ubiquitination. Overexpression of cFLIP is observed in several cancers and is associated with resistance to death receptor–mediated apoptosis and to TRAIL-based therapies. Targeting CFLAR or specific cFLIP isoforms is being explored to sensitize tumor cells to apoptosis in preclinical settings.