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

Abstract

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 ...

Tripartite Motif-Containing Protein 38 Negatively Regulates TLR3/4- and RIG-I–Mediated IFN-β Production and Antiviral Response by Targeting NAP1

“…TRIM23 has been shown to catalyze K27-linked ubiquitination of NEMO, which is crucial for IRF3 and NF-kB activation downstream of TLR3 and RIG-I (34). TRIM21 has been shown to mediate K48-linked ubiquitination of various IRFs, and thereby directly inhibit production of type I IFNs (35)(36)(37).…”

Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?

“…Both TRIM27 and TRIM21 have been shown to interact with the IKKs repressing their activity and as a result pro-inflammatory cytokine production [27,88]. TRIM21 also interacts with the IRFs 3, 7,8, each interaction resulting in repression of NFKB and IFN promoter activity [85,[109][110][111]. On the contrary, some TRIMs function as positive regulators of these pathways.…”

Precision autophagy directed by receptor regulators – emerging examples within the TRIM family

“…This is also reflected in the related ability of TRIM21 to degrade inhibitor of NF-κB kinase (IKKβ, encoded by IKBKB) through autophagy (Niida et al, 2010). TRIM21 also targets other factors that are responsible for type-I IFN activation, including IRF-5, IRF-7 and IRF-8, for degradation through proteasomal or, thus far, unknown mechanisms (Higgs et al, 2008(Higgs et al, , 2010Espinosa et al, 2009;Yoshimi et al, 2009;Young et al, 2011;Lazzari et al, 2014). TRIMs are often described as autoantigens in autoimmune diseases and cancers, including TRIM21 and TRIM68 in SLE and Sjögren syndrome (Der et al, 1998;Billaut-Mulot et al, 2001), TRIM33 in dermatomyositis and the associated paraneoplastic phenomena (Targoff et al, 2006;Fujimoto et al, 2012), TRIM19 in primary biliary cirrhosis (Stinton et al, 2011), and TRIM28 in colon cancer (Kijanka et al, 2010;Hector et al, 2012) and dermatomyositis (Satoh et al, 2012).…”