Tripartite Motif-Containing Protein 28 Is a Small Ubiquitin-Related Modifier E3 Ligase and Negative Regulator of IFN Regulatory Factor 7

Abstract

Interferon regulatory factor 7 (IRF7) is a potent transcription factor of type I interferons (IFNs) and IFN stimulated genes (ISGs) and is known as the master regulator of type I IFN-dependent immune responses. Because excessive responses could harm the host, IRF7 itself is delicately regulated at the transcriptional, translational, and posttranslational levels. Modification of IRF7 by small ubiquitin-related modifiers (SUMOs) has been shown to regulate IFN expression and antiviral responses negatively, but the specific E3 ligase needed for IRF7 SUMOylation has remained unknown. As reported here, we have identified the tripartite motif–containing (TRIM) protein 28 (TRIM28) as a binding partner of IRF7. We have demonstrated that TRIM28 also interacts with the SUMO E2 enzyme and increases SUMOylation of IRF7 both in vivo and in vitro, suggesting it acts as a SUMO E3 ligase of IRF7. Unlike the common SUMO E3 ligase, protein inhibitor of activated STAT 1(PIAS1), the E3 activity of TRIM28 is specific to IRF7, because it has little effect on IRF7’s close relative IRF3. TRIM28 is therefore, so far as we know, the first IRF7-specific SUMO E3 reported. TRIM28-mediated SUMOylation of IRF7 is increased during viral infection, and SUMOylation of transcription factors usually results in transcriptional repression. Overexpression of TRIM28 therefore inhibits IRF7 transactivation activity, whereas knockdown of TRIM28 has the opposite effect and potentiates IFN production and antiviral responses. Collectively, our results suggest that TRIM28 is a specific SUMO E3 ligase and negative regulator of IRF7.

Functions of the two zebrafish MAVS variants are opposite in the induction of IFN1 by targeting IRF7

“…Guanylate binding protein 4 (GBP4) disrupts the interactions between TRAF6 and IRF7, leading to reduction of TRAF6-mediated IRF7 ubiquitination [42]. Tripartite motif-containing protein 28 (TRIM28) mediates SUMOylation (post-translational modification mediated by small ubiquitin-like modifier (SUMO) proteins) of IRF7 and inhibits IRF7 transactivation activity [43]. In fish, although the mechanisms of negative regulation of IFN expression is not as clear as in mammals, a slice of reports suggested that fish also contains the brake system.…”

Erase–Maintain–Establish: Natural Reprogramming of the Mammalian Epigenome

“…Additional insights to TRIM28 function in vivo were gained from studies in preimplantation embryos (Satou 2001;Li et al 2003;Satou et al 2004;Wang et al 2005Wang et al , 2007Jin et al 2007;Tsuruma et al 2007;Kamitani et al 2008Kamitani et al , 2011Peng et al 2009;Seki et al 2010;Liang et al 2011;Maruyama et al 2011;Huang et al 2013). TRIM28 attracts chromatin writers and readers (right) (Nielsen et al 1999;Ryan et al 1999;Schultz et al 2001Schultz et al , 2002Quenneville et al 2011;Zuo et al 2012).…”

“…2;Satou 2001;Li et al 2003;Satou et al 2004;Wang et al 2005Wang et al , 2007Jin et al 2007;Tsuruma et al 2007;Kamitani et al 2008Kamitani et al , 2011Peng et al 2009;Seki et al 2010;Liang et al 2011;Maruyama et al 2011;Huang et al 2013). For most of these, the KRAB-ZFPs included, TRIM28 functions as a co-repressor down-regulating gene transcription by its heterochromatin-inducing activity at its target sites (Iyengar and Farnham 2011;Cheng 2014).…”

Differential control of retrovirus silencing in embryonic cells by proteasomal regulation of the ZFP809 retroviral repressor

“…The above results suggest that full-length ZFP809 protein in differentiated cells is a target for ubiquitin-dependent protein degradation. TRIM28, which interacts with ZFP809, is a RING domain-containing protein and known to serve as an E3 ligase for transfer of ubiquitin (41). RING domain proteins often bind to Cullins, a protein family serving as a scaffold for the assembly of a complex that mediates protein degradation (42).…”