FADD

3OQ9, 1A1W, 1A1Z, 1E3Y, 1E41, 2GF5, 3EZQ877214082ENSG00000168040ENSMUSG00000031077Q13158Q61160NM_003824NM_010175NP_003815NP_034305FAS-associated death domain protein, also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans.

[4] FADD is an adaptor protein that bridges members of the tumor necrosis factor receptor superfamily, such as the Fas-receptor, to procaspases 8 and 10 to form the death-inducing signaling complex (DISC) during apoptosis.

These are inactive molecules, but when bought into close proximity with other procaspases of the same type, autocatalytic cleavage occurs at an aspartate residue within their own structures, resulting in an activated protein.

[12] The activated caspases can go on to cleave intracellular proteins such as inhibitor of caspase-activated DNase (ICAD), which ultimately leads to apoptosis of the cell.

[14] Apoptosis can also be triggered by binding of a ligand to tumor necrosis factor receptor 1 (TNFR1); however, the mechanism by which this occurs is slightly more complex.

In accordance, cells deficient in FADD induce necroptosis as they are unable to recruit and activate procaspase 8.

This regulation is dependent on phosphorylation of FADD on Serine 194, which is carried out by Casein Kinase 1a (CKIα).

[23] Activation of nuclear factor kappa B (NFκB) signalling leads to transcription of various proinflammatory cytokines as well as anti-apoptotic genes.

This activates a signalling pathway which results in translocation of NFκB to the nucleus, where it induces the transcription of the inflammatory cytokines.

FADD can interfere with the interaction between MyD88 and IRAK, by binding to MyD88 via its DD and therefore this disrupts the cascade which would lead to NFκB translocation and inflammation.

Without FADD, PKC remains active and is able to continue signalling cascades leading to processes including cytoskeletal rearrangements and cell motility.

[27] Recent research has also shown that it may have a role in regulating glucose levels and the phosphorylated form of FADD is important for this function.

[33] Increased levels of FADD were found in the leukocytes of patients with relapsing remitting multiple sclerosis, contributing to inflammation.

[34] In rheumatoid arthritis, it is thought that stimulation of Fas receptors on macrophages, leads to formation of the FADD containing DISCs.

Formation of these sequesters FADD away from MyD88 allowing MyD88 to interact with IRAK and induce the enhanced inflammation associated with this disease.

[25] However, there is significant upregulation of FADD in ovarian cancer[36] and head and neck squamous cell carcinoma.

[38] Taxol is a drug used in anticancer therapies due to its ability to interfere with microtubule assembly, which leads to cell cycle arrest.

[40] However, high levels of phosphorylated FADD have been correlated with a poor prognosis in many cancers such as that of the head and neck.

[41] For example, It has been suggested that inhibition of FADD might work as a potential targeted therapy for drug-resistant ovarian cancer.

Diagram shows the extrinsic apoptotic pathway whereby the Fas receptor (FasR)on one cell is stimulated by the Fas ligand (FasL)on a different cell, recruiting FADD to the FasR via an interaction between the death domains (DD) of both molecules. Procaspase 8 is recruited to FADD and interacts via the death effector domains (DED) of both molecules. This results in the cleavage and activation of procaspase 8, forming caspase 8, which goes on to cleave and activate other caspases such as procaspase 3 to initiate the caspase cascade which leads to cell death
Extrinsic apoptosis pathway: The Fas receptor (FasR) is stimulated by Fas ligand (FasL), recruiting FADD to the FasR via an interaction between the death domains (DD) of both molecules. Procaspase 8 is recruited to FADD and interacts via the death effector domains (DED) of both molecules. This results in the cleavage and activation of procaspase 8, forming caspase 8, which goes on to cleave and activate other caspases such as procaspase 3 to initiate the caspase cascade which leads to cell death.
Regulation of FADD by MKRN1: MKRN1 ubiquitinylates FADD targeting it for degradation by the 26S proteosome. As it is degraded, FADD can no longer bind to the Fas receptor to induce apoptosis when the Fas ligand binds to the Fas receptor. The Fas ligand and Fas receptor are on separate cells.
Regulation of FADD by MKRN1: MKRN1 ubiquitinylates FADD targeting it for degradation by the 26S proteosome. As it is degraded, FADD can no longer bind to the Fas receptor (Fas R) to induce apoptosis.