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    • Introduction Infection of cells by microorganisms activates

    2019-11-05

    Introduction Infection of mitoxantrone by microorganisms activates the inflammatory response. The initial sensing of infection is mediated by innate pattern recognition receptors (PRRs)including Toll-like receptors(TLRs) (Kawai and Akira, 2010; O’Neill et al., 2013).Toll-like receptor 4 (TLR4) is one of the well-studied PRRs for the bacterial lipopolysaccharide (LPS) (Rosadini and Kagan, 2016; Kuzmich et al., 2017),which plays a pivotal role in the initiation and elimination of invading pathogens as aberrant activation of TLR4 has been closely associated with inflammatory and autoimmune diseases (Mukherjee et al., 2016). It has been well-documented that activation of TLR4 depends on the sequential binding of LPS-binding protein (LBP),CD14 and MD-2,consequently forming the TLR4-MD2-LPS complex and resulting in the initiation of signal transduction through the MyD88-dependent or TRIF-dependent pathways (Park et al., 2009; Peri and Piazza, 2012; Guven-Maiorov et al., 2015). MyD88-mediated signaling which occurs mainly at the plasma membrane may activate several transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). These transcription factors thereby induce the transcription and release of proinflammatory cytokines including tumor necrosis factor alpha (TNF-α), IL-1β and IL-6 (Molteni et al., 2016; Vijay, 2018; Blasius and Beutler, 2010). Unlike the MyD88-dependent signaling, activation of TRIF-dependent pathway usually occurs at the endosomal compartment initially by recruiting and phosphorylating IFN regulatory factor 3 (IRF3) (Liu et al., 2015). The Phosphorylated IRF3 then dimerizes and translocates to the nucleus to induce the transcription of IFN-β (Honda et al., 2006). The proinflammatory cytokines and type I interferons (IFNs) produced by either way could not only directly suppress the microbial infections, but also activate the adaptive immunity to eliminate the invading pathogens. Tripartite motif proteins (TRIMs) which belong to E3 ligase family play important roles in some aspects of the immune system, including innate response, adaptive immunity and antimicrobial autophagy. There have been more than 80 TRIM genes reported in mammals (Hatakeyama, 2017). The TRIM proteins are named as their conserved RBCC domain which includes an E3 ligase domain(R) of areally interesting new gene (RING), one or two B-box domains (B) and a coiled-coil domain (CC) (Ebner et al., 2017; Reymond et al., 2001). Recently, TRIMs have been described to assemble signaling complexes, alter subcellular localization, mediate proteolytic degradation, or modulate the host’s transcription or protein composition by coordinating the ubiquitination of target proteins (Rajsbaum et al., 2014; Versteeg et al., 2014; Esposito et al., 2017). Lines of evidence have shown that microbial pathogens might exploit the ubiquitin modification to evade the host immune system (Jiang and Chen, 2011). Recent studies also show that many TRIM proteins serve as regulators of innate immunity via PRRs such as TLR and RIG-I or via cytokines such as IFN and TNF-α during the signaling transduction (Jiang and Chen, 2011). As examples, TRIM52 overexpression could promote the activation of the NF-κB pathway, and then lead to an increased expression of TNF-α and IL-6 (Fan et al., 2017). TRIM38 could interact with TRAF6 and TRIF, and subsequently mediate K48-linked poly-ubiquitination of TRAF6 and TRIF for proteasome degradation (Zhao et al., 2012). TRIM39 might negatively regulate the NF-κB signaling in collaboration with Cactin induced by TNF-α (Suzuki et al., 2016). TRIM7 was first identified as glycogenin interacting protein (GNIP) and has been reportedly involved in glycogen synthesis. Knockdown of Trim7 in the primary(KP) lung tumor cells could reduce cell proliferation and decrease the tumor growth in xenograft experiments. Consistently, deletion of Trim7 in an established xenograft tumor also leads to a reduced tumor growth, indicating that intervention of the MSK1/Trim7 RING domain/AP-1 co-activator 1 (RACO-1) signaling pathway may be a potential strategy for the tumor treatment (Chakraborty et al., 2015). However, the role of TRIM7 in the TLR-mediated signaling pathway has not been clarified yet.