Fas Apoptosis Inhibitory Molecule Contains a Novel β-Sandwich in Contact with a Partially Ordered Domain

Hemond, Michael; Rothstein, Thomas L.; Wagner, Gerhard

doi:10.1016/j.jmb.2009.01.004

Cited by 16 publications

(25 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Structural FAIM‐S studies showed that it contains two independently folding domains (Hemond et al . ). Nuclear magnetic resonance approaches demonstrated that the C‐terminal domain of FAIM‐S folds as a non‐conventional β‐sandwich, and the crystal structure of the N‐terminal domain revealed a similar conformation containing eight antiparallel β‐strands (Li et al .…”

Section: Faim1mentioning

confidence: 97%

Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system

Planells-Ferrer

Urresti

Coccia

et al. 2016

Journal of Neurochemistry

View full text Add to dashboard Cite

The importance of death receptor (DR) signaling in embryonic development and physiological homeostasis is well established, as is the existence of several molecules that modulate DRs function, among them Fas Apoptotis Inhibitory Molecules. Although FAIM1, FAIM2, and FAIM3 inhibit Fas-induced cell death, they are not structurally related, nor do they share expression patterns. Moreover, they inhibit apoptosis through completely different mechanisms. FAIM1 and FAIM2 protect neurons from DR-induced apoptosis and are involved in neurite outgrowth and neuronal plasticity. FAIM1 inhibits Fas ligand-and tumor necrosis factor alpha-induced apoptosis by direct interaction with Fas receptor and through the stabilization of levels of X-linked inhibitor of apoptosis protein, a potent anti-apoptotic protein that inhibits caspases. Low FAIM1 levels are found in Alzheimer's disease, thus sensitizing neurons to tumor necrosis factor alpha and prompting neuronal loss. FAIM2 protects from Fas by direct interaction with Fas receptor, as well as by modulating calcium release at the endoplasmic reticulum through interaction with Bcl-xL. Several studies prove the role of FAIM2 in diseases of the nervous system, such as ischemia, bacterial meningitis, and neuroblastoma. The less characterized member of the FAIM family is FAIM3, which is expressed in tissues of the digestive and urinary tracts, bone marrow and testes, and restricted to the cerebellum in the nervous system. FAIM3 protects against DR-induced apoptosis by inducing the expression of other DRantagonists such as CFLAR or through the interaction with the DR-adaptor protein Fas-associated via death domain. FAIM3 null mouse models reveal this protein as an important mediator of inflammatory autoimmune responses such as those triggered in autoimmune encephalomyelitis. Given the

show abstract

Section: Faim1mentioning

confidence: 97%

Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system

Planells-Ferrer

Urresti

Coccia

et al. 2016

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…This suggests that the N-terminal domain in general, or the nonspliced additional N-terminal 22 amino acids of FAIM-L in particular, are regulatory in nature and influence the activity of a more C-terminal effector motif. Because the evolutionarily conserved FAIM-S sequence contains no known effector motifs, and because the FAIM-S structure expresses a unique fold that has no known homologues (54), it is highly likely that, when defined, the FAIM-S effector domain will be found to be a currently unrecognized and novel sequence. The mechanism by which FAIM-S effects enhancement of CD40 signaling in B cells remains unknown; however, inasmuch as NF- κ B stimulates IRF4 expression and IRF4 inhibits BCL-6 expression, it appears that the various facets of FAIM activity are determined by its amplification of NF- κ B activation.…”

Section: Discussionmentioning

confidence: 99%

Fas Apoptosis Inhibitory Molecule Enhances CD40 Signaling in B Cells and Augments the Plasma Cell Compartment

Kaku

Rothstein²

2009

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Fas apoptosis inhibitory molecule (FAIM) was cloned as a mediator of Fas resistance that is highly evolutionarily conserved but contains no known effector motifs. In this study, we report entirely new functions of FAIM that regulate B cell signaling and differentiation. FAIM acts to specifically enhance CD40 signaling for NF-κB activation, IRF-4 expression, and BCL-6 down-regulation in vitro, but has no effect on its own or in conjunction with LPS or anti-Ig stimulation. In keeping with its effects on IRF-4 and BCL-6, FAIM overexpression augments the plasma cell compartment in vivo. These results indicate that FAIM is a new player on the field of B cell differentiation and acts as a force multiplier for a series of events that begins with CD40 engagement and ends with plasma cell differentiation.

show abstract

“…We concluded that Faim promoter activity is regulated by IRF4 because: (1) the Faim promoter contains 3 IRF binding sites; (2) Faim promoter activity is lost following deletion or mutation of all three IRF binding sites (Fig. 1); (3) Faim promoter activity is enhanced by concurrent expression of IRF4 (Fig. 1); (4) IRF4 expression precedes FAIM expression in primary B cells stimulated ex vivo (Fig.…”

Section: Discussionmentioning

confidence: 95%

“…The Faim gene is located at 9f1 in mice (and at the syntenic region 3q22 in humans) and encodes an ~1.2-kb transcript that produces a 179-aa protein of ~20 kDa (1, 2). FAIM contains a highly evolutionarily conserved sequence (from worm to fly to mouse to human) that is arranged in a unique β sandwich structure and contains no known effector motifs (3). …”

mentioning

confidence: 99%

Fas Apoptosis Inhibitory Molecule Expression in B Cells Is Regulated through IRF4 in a Feed-Forward Mechanism

Kaku

Rothstein

2009

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Fas apoptosis inhibitory molecule (FAIM) was originally cloned as an inhibitor of Fas-mediated apoptosis in B cells that has been reported to affect multiple cell types. Recently, we found that FAIM enhances CD40L-mediated signal transduction, including induction of IFN regulatory factor (IRF)4, in vitro and augments plasma cell production in vivo. These results have keyed interest in the regulation of FAIM expression, about which little is known. Here, we show that Faim is regulated by IRF4. The Faim promoter contains three IRF binding sites, any two of which promote Faim expression. Faim promoter activity is lost following mutation of all three IRF binding sites, whereas activity of the full promoter is enhanced by concurrent expression of IRF4. In stimulated primary B cells, IRF4 expression precedes FAIM expression, IRF4 binds directly to the Faim promoter, and loss of IRF4 results in the failure of stimulated Faim up-regulation. Finally, FAIM is preferentially expressed in germinal center B cells. Taken together, these results indicate that FAIM expression is regulated through IRF4 and that this most likely occurs as part of germinal center formation. Because FAIM enhances CD40-induced IRF4 expression in B cells, these results suggest that induction of FAIM initiates a positive reinforcing (i.e., feed-forward) system in which IRF4 expression is both enhanced by FAIM and promotes FAIM expression.

show abstract

Fas Apoptosis Inhibitory Molecule Contains a Novel β-Sandwich in Contact with a Partially Ordered Domain

Cited by 16 publications

References 26 publications

Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system

Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system

Fas Apoptosis Inhibitory Molecule Enhances CD40 Signaling in B Cells and Augments the Plasma Cell Compartment

Fas Apoptosis Inhibitory Molecule Expression in B Cells Is Regulated through IRF4 in a Feed-Forward Mechanism

Contact Info

Product

Resources

About