CFLAR Human

The CASP8 and FADD-like apoptosis regulator, also known as CFLAR or c-FLIP, is a protein that plays a crucial role in the regulation of apoptosis, inflammation, and cellular differentiation. This protein is encoded by the CFLAR gene in humans and is involved in various cellular processes, including the inhibition of apoptosis and the modulation of immune responses.

CFLAR is structurally similar to caspase-8 (CASP8) and contains two death effector domains (DEDs) at its N-terminus, which allow it to interact with other proteins involved in apoptotic signaling pathways. The protein exists in multiple isoforms, with the two main forms being c-FLIP(L) and c-FLIP(S). These isoforms differ in their C-terminal regions and have distinct functions in the regulation of apoptosis.

• c-FLIP(L): This isoform can inhibit apoptosis by binding to the death-inducing signaling complex (DISC) and preventing the activation of caspase-8. It acts as a competitive inhibitor of caspase-8, thereby blocking the apoptotic signaling cascade.
• c-FLIP(S): This isoform lacks the C-terminal caspase-like domain and functions as a dominant-negative inhibitor of apoptosis. It can also interact with DISC and inhibit the activation of caspase-8, but its mechanism of action is different from that of c-FLIP(L).

Apoptosis, or programmed cell death, is a vital process for maintaining cellular homeostasis and eliminating damaged or infected cells. The extrinsic pathway of apoptosis is initiated by the binding of death ligands, such as Fas ligand (FasL) or tumor necrosis factor (TNF), to their respective death receptors on the cell surface. This interaction leads to the formation of the DISC, which recruits and activates caspase-8.

CFLAR plays a critical role in regulating this pathway by inhibiting the activation of caspase-8. By binding to DISC, CFLAR prevents the cleavage and activation of caspase-8, thereby blocking the downstream apoptotic signaling cascade. This inhibition of apoptosis is essential for the survival of certain cell types, such as immune cells, during immune responses.

In addition to its role in apoptosis, CFLAR is also involved in the regulation of inflammation. Caspase-8, which is inhibited by CFLAR, can promote the expression of pro-inflammatory cytokines and other inflammatory mediators. By inhibiting caspase-8, CFLAR can modulate the inflammatory response and prevent excessive inflammation.

The dysregulation of CFLAR expression and function has been implicated in various diseases, including cancer, autoimmune disorders, and neurodegenerative diseases. Overexpression of CFLAR has been observed in several types of cancer, where it contributes to the resistance of cancer cells to apoptosis and promotes tumor progression. Conversely, reduced expression of CFLAR has been associated with increased susceptibility to autoimmune diseases and neurodegenerative disorders.

Given its critical role in regulating apoptosis and inflammation, CFLAR is a potential therapeutic target for the treatment of various diseases. Strategies aimed at modulating CFLAR expression or function could be used to enhance apoptosis in cancer cells or to reduce inflammation in autoimmune and inflammatory diseases.