FADD self-association is required for stable interaction with an activated death receptor

Sandu, Cristinel; Morisawa, Gaku; Wegorzewska, Iga N.; Huang, Tao; Arechiga, Adrian F.; Hill, Jennifer; Kim, T; Walsh, Craig M.; Werner, M.D.

doi:10.1038/sj.cdd.4401966

Cited by 53 publications

(66 citation statements)

References 38 publications

(69 reference statements)

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“…As a result, the protein was easily purified with high purity. Consistent with the previous studies (30,31), the DED-deficient C-FADD existed as a monomer. This result further supports the notion that FADD usually exists in monomer form, and only upon apoptotic stimulation, it participates in the formation of DISC (the death-inducing signaling complex) in trimer form via interacting with TNFR by DD domain and associating with procaspase-8 by DED domain.…”

Section: Discussionsupporting

confidence: 92%

“…Due to the difficulty in the expression and purification of the whole FADD molecule and its instability, no full-length FADD could be obtained to qualify for structural determination (23). In the present paper, the DED domain, which was supposed to mediate FADD self-association, was deleted from mFADD (30,31). The recombinant mFADD contains DD domain and CTD domain.…”

Section: Discussionmentioning

confidence: 95%

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Expression, Purification and Characterization of C-FADD

Chen

Huang

et al. 2009

Cell Mol Immunol

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FADD is an important proapoptotic adaptor in death receptor-induced apoptosis. Recently, FADD has been found to participate in a variety of non-apoptotic processes, such as development, cell cycle progression and survival. Its non-apoptotic activities were regulated by the phosphorylated status of the serine residue located at the C-terminal region, a domain distinct from the proapoptotic function related DED and DD domains. However, due to the difficulties in expression and crystallization of natural FADD, by far the molecular structures of all FADD variants did not contain the C-terminal region. To elucidate the structure-function relationship of C-terminal region, we need to obtain an FADD variant that containing C-terminal region. In this study, mouse FADD (80-205) containing DD domain and C-terminal region, designated as C-FADD, was expressed in E. coli with His-tag at the N-terminus and purified by Ni 2+ affinity chromatography. The purified protein existed as a homogenous monomer in glutaraldehyde cross-linking analysis and exhibited a typical α-helix spectrum in CD (circular dichroism) assay. In vitro His-tag pull-down assay demonstrated that the purified C-FADD possessed the CK I-binding activity which was important for its non-apoptotic function. Cellular & Molecular Immunology. 2009;6(4):295-301.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 95%

Expression, Purification and Characterization of C-FADD

Chen

Huang

et al. 2009

Cell Mol Immunol

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“…Furthermore, the FADDdd protein is not truly a dominant-negative protein, as previously thought. The level of transgenic FADDdd protein is at least 100-fold that of endogenous FADD protein expression (40); expression of FADDdd at physiological levels failed to suppress Fas-induced apoptosis (40). It is not clear whether the defective proliferation of Caspase-8-deficient T cells can be rescued by an autophagic inhibitor or not.…”

Section: Necroptosis Of Proliferating Fadd-deficient T Cells Is Not Dmentioning

confidence: 99%

Fas-associated death domain (FADD) is a negative regulator of T-cell receptor–mediated necroptosis

Osborn

Diehl

Han

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

139

111

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Cell death is an important mechanism to limit uncontrolled T-cell expansion during immune responses. Given the role of deathreceptor adapter protein Fas-associated death domain (FADD) in apoptosis, it is intriguing that T-cell receptor (TCR)-induced proliferation is blocked in FADD-defective T cells. Necroptosis is an alternate form of death that can be induced by death receptors and is linked to autophagy. It requires the death domain-containing kinase RIP1 and, in certain instances, RIP3. FADD and its apoptotic partner, Caspase-8, have also been implicated in necroptosis. To accurately assess the role of FADD in mature T-cell proliferation and death, we generated a conditional T-cell-specific FADD knockout mouse strain. The T cells of these mice develop normally, but lack FADD at the mature stage. FADD-deficient T cells respond poorly to TCR triggering, exhibit slow cell cycle entry, and fail to expand over time. We find that programmed necrosis occurs during the late stage of normal T-cell proliferation and that this process is greatly amplified in FADD-deficient T cells. Inhibition of necroptosis using an inhibitor of RIP1 kinase activity rescues the FADD knockout proliferative defect. However, TCR-induced necroptosis did not appear to require autophagy or involve RIP3. Consistent with their defective CD8 T-cell response, these mice succumb to Toxoplasma gondii infection more readily than wild-type mice. We conclude that FADD constitutes a mechanism to keep TCR-induced programmed necrotic signaling in check during early phases of T-cell clonal expansion.apoptosis | RIP1 | RIP3 | Caspase-8 | proliferation

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“…FADD contains two domains that facilitate protein-protein interactions; that is, the death-effector domain (DED) and the death domain (5,6). The FADD DED participates in self-association and binding to procaspase-8, whereas the death domain interacts with the death receptors, TRADD or RIP1 (5,(7)(8)(9).…”

Section: Fas-associated Death Domain (Fadd)mentioning

confidence: 99%

“…Extensive FADD DED mutagenesis was previously conducted to reveal residues, specifically Phe-25, Leu-28, and Lys-33, that are important for FADD self-association, CD95 receptor binding, and pro-caspase-8 interaction (8,9). A complex with TRIM21 was detected with the L28E FADD mutant, indicating that FADD dimerization is not necessary to interact with TRIM21 (data not shown).…”

Section: Fadd Interacts With Trim 21 But Not the Other Closelymentioning

confidence: 99%

Fas-associated Death Domain (FADD) and the E3 Ubiquitin-Protein Ligase TRIM21 Interact to Negatively Regulate Virus-induced Interferon Production

Young

Sermwittayawong

Kim

et al. 2011

Journal of Biological Chemistry

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The production of cytokines such as type I interferon (IFN) is an essential component of innate immunity. Insufficient amounts of cytokines lead to host sensitivity to infection, whereas abundant cytokine production can lead to inflammation. A tight regulation of cytokine production is, thus, essential for homeostasis of the immune system. IFN-␣ production during RNA virus infection is mediated by the master transcription factor IRF7, which is activated upon ubiquitination by TRAF6 and phosphorylation by IKK⑀ and TBK1 kinases. We found that Fas-associated death domain (FADD), first described as an apoptotic protein, is involved in regulating IFN-␣ production through a novel interaction with TRIM21. TRIM21 is a member of a large family of proteins that can impart ubiquitin modification onto its cellular targets. The interaction between FADD and TRIM21 enhances TRIM21 ubiquitin ligase activity, and together they cooperatively repress IFN-␣ activation in Sendai virus-infected cells. FADD and TRIM21 can directly ubiquitinate IRF7, affect its phosphorylation status, and interfere with the ubiquitin ligase activity of TRAF6. Conversely, a reduction of FADD and TRIM21 levels leads to higher IFN-␣ induction, IRF7 phosphorylation, and lower titers of RNA virus of infected cells. We conclude that FADD and TRIM21 together negatively regulate the late IFN-␣ pathway in response to viral infection. Fas-associated death domain (FADD)5 is an adaptor protein known to be crucial for the mammalian cell extrinsic pathway of apoptosis. Ligand engagement of the tumor necrosis factor receptor (TNF-R) family of death receptors, which include Fas, TNF-R1, and TRAIL-R, leads to recruitment of FADD and caspase-8 to form a death-inducing complex (1-4). For Fas, FADD is directly recruited to the cytoplasmic tail and is part of the membrane-associated Fas⅐FADD⅐caspase-8 complex. In contrast, TNF-R1 activation leads to the assembly of a cytoplasmic complex that consists of either TRADD⅐FADD⅐caspase-8 or RIP1⅐FADD⅐caspase-8 (3). FADD contains two domains that facilitate protein-protein interactions; that is, the death-effector domain (DED) and the death domain (5, 6). The FADD DED participates in self-association and binding to procaspase-8, whereas the death domain interacts with the death receptors, TRADD or RIP1 (5, 7-9).Accumulating evidence also points to a role for FADD in innate immunity. In Drosophila melanogaster, FADD is part of the immune deficiency pathway required for the Drosophila immune defense against the Gram-negative bacteria (10 -12). Immune deficiency, the Drosophila equivalent of mammalian RIP1, interacts with Drosophila FADD and caspase-8 to initiate the NF-B pathway, leading to production of Drosomycin, an anti-bacterial peptide. Drosophila deficient in FADD expression succumb to infection by Gram-negative bacteria (12). In mice, the absence of FADD or caspase-8 prevents TLR-3/4 (Toll-like receptor)-induced B cell proliferation (13,14). In human and mouse fibroblasts, FADD was implicated in the interferon (IFN) pathway ...

show abstract

FADD self-association is required for stable interaction with an activated death receptor

Cited by 53 publications

References 38 publications

Expression, Purification and Characterization of C-FADD

Expression, Purification and Characterization of C-FADD

Fas-associated death domain (FADD) is a negative regulator of T-cell receptor–mediated necroptosis

Fas-associated Death Domain (FADD) and the E3 Ubiquitin-Protein Ligase TRIM21 Interact to Negatively Regulate Virus-induced Interferon Production

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