CFLAR - CASP8 and FADD-like apoptosis regulator | Elisa - Clia - Antibody - Protein

Background

CASP8 and FADD-like apoptosis regulator (CFLAR), also known as c-FLIP (cellular FLICE-like inhibitory protein), is a critical regulator of apoptosis and necroptosis, acting predominantly as an inhibitor of caspase-8. CFLAR is essential for controlling the balance between cell survival and programmed cell death, which is crucial for maintaining tissue homeostasis and immune responses. Apoptosis is a highly regulated process of programmed cell death essential for development, immune function, and the elimination of damaged or diseased cells. CFLAR was identified due to its homology with caspase-8 (FLICE) and its ability to interact with FADD (Fas-Associated protein with Death Domain), a key adaptor protein in death receptor signaling pathways.

CFLAR exists in multiple isoforms, with c-FLIPL (long form) and c-FLIPS (short form) being the most studied. These isoforms are generated through alternative splicing and have distinct regulatory roles in apoptotic signaling. By modulating the activity of caspase-8, CFLAR prevents the induction of apoptosis via death receptors such as Fas, TNFR1, and TRAIL receptors, thereby influencing immune responses and cell fate decisions.

Protein Structure

CFLAR’s structure is integral to its function as an apoptosis regulator:

• Death Effector Domains (DEDs): CFLAR contains two N-terminal DEDs, which are responsible for interactions with other DED-containing proteins such as FADD and procaspase-8. These interactions are crucial for the formation of the Death-Inducing Signaling Complex (DISC).
• Caspase-like domain: The c-FLIPL isoform contains a caspase-like domain similar to caspase-8 but lacks catalytic activity due to critical amino acid substitutions. This domain enables it to dimerize with caspase-8 and inhibit its activation.
• Absence of catalytic activity: Unlike caspase-8, CFLAR does not possess proteolytic activity, which is essential for its role as an inhibitor rather than an executor of apoptosis.

Classification and Subtypes

CFLAR is primarily classified based on its isoforms:

• c-FLIPL (long form): Contains both DEDs and the caspase-like domain. It acts as a dominant-negative inhibitor of caspase-8 by forming inactive heterodimers.
• c-FLIPS (short form): Contains only the DEDs and lacks the caspase-like domain. It inhibits apoptosis by preventing the recruitment and activation of caspase-8 at the DISC.
• c-FLIPR (Raji form): An isoform similar to c-FLIPS but with slight variations in its sequence and function.

Function and Biological Significance

CFLAR is essential for several cellular processes:

• Regulation of Apoptosis: By inhibiting caspase-8 activation, CFLAR prevents the initiation of the apoptotic cascade triggered by death receptors, thus promoting cell survival.
• Necroptosis Modulation: CFLAR can also influence necroptosis, a form of programmed necrosis, by regulating the activity of RIPK1 and RIPK3 kinases.
• Immune Response: CFLAR expression modulates immune cell survival, proliferation, and activation, impacting immune responses and homeostasis.
• Cellular Homeostasis: By balancing apoptosis and cell survival, CFLAR maintains tissue homeostasis and protects against inappropriate cell death in various physiological contexts.

Clinical Issues

Dysregulation of CFLAR is implicated in several diseases:

• Cancer: Overexpression of CFLAR is common in various cancers, where it contributes to resistance against apoptosis-inducing treatments, promoting tumor cell survival and progression.
• Autoimmune Diseases: Abnormal CFLAR activity can result in insufficient apoptosis of immune cells, leading to autoimmune conditions where the immune system attacks the body's own tissues.
• Cardiovascular Diseases: CFLAR dysregulation may influence cell death pathways in cardiac tissues, impacting conditions such as ischemia-reperfusion injury and heart failure.

Summary

CFLAR (c-FLIP) is a crucial regulator of apoptosis and necroptosis, primarily functioning as an inhibitor of caspase-8. The protein contains two DEDs and, in the long isoform (c-FLIPL), a caspase-like domain without catalytic activity. CFLAR prevents apoptosis by inhibiting caspase-8 activation at the DISC, thereby playing a significant role in cell survival and immune regulation. Its dysregulation is associated with various pathological conditions, including cancer, autoimmune diseases, and cardiovascular disorders. Understanding the precise mechanisms by which CFLAR controls cell death and survival pathways continues to be a critical area of research, offering potential therapeutic targets for a range of diseases.