cFLIPL

cFLIPL, the long isoform of cellular FLICE-like inhibitory protein (cFLIP), is a key regulator of death receptor signaling and apoptosis. In humans, cFLAR is encoded by the CFLAR gene and through alternative splicing yields several isoforms, among which cFLIP_L (cFLIPL) is the long form. Structurally, cFLIP_L contains two N-terminal death effector domains (DEDs) and a C-terminal caspase-like domain that is catalytically inactive, classifying it as a pseudo-caspase.

Functionally, cFLIP_L modulates the extrinsic apoptotic pathway by localizing to the death-inducing signaling complex (DISC) formed downstream of receptors such as Fas, TNFR1, and TRAIL receptors. There, it forms heterodimers with procaspase-8, inhibiting full activation of caspase-8 and thereby blocking the caspase cascade that leads to apoptosis. The outcome can depend on expression levels and cellular context: at certain levels, cFLIP_L may permit limited caspase-8 activity that can favor non-apoptotic signaling, including pathways linked to cell survival and inflammation. Additionally, cFLIP_L influences the balance between apoptosis and necroptosis by modulating caspase-8 activity, affecting downstream signaling in death receptor networks.

Expression and regulation of cFLIP_L are coordinated with other CFLAR isoforms, such as cFLIP_S and cFLIP_R, produced by alternative splicing. These shorter isoforms primarily act as inhibitors of caspase-8 at the DISC due to the absence of the pseudo-caspase domain. Regulation of CFLAR/cFLIP expression is influenced by inflammatory signals, stress responses, and transcriptional programs including NF-κB and p53 pathways.

Clinical relevance centers on cFLIP_L’s role in cancer and immune regulation. Overexpression of cFLIP_L has been observed in various tumors and is associated with resistance to death receptor–mediated therapies, making CFLAR a potential target to sensitize cancer cells to apoptosis-inducing treatments.