Abstract
A systematic and flexible immunoregulatory network is required to ensure the proper outcome of antiviral immune signaling and maintain homeostasis during viral infection. Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2), a novel immunoregulatory protein, has been extensively studied in inflammatory response, apoptosis, and cancer. However, the function of TIPE2 in antiviral innate immunity is poorly clarified. In this study, we reported that the expression of TIPE2 declined at the early period and then climbed up in macrophages under RNA virus stimulation. Knockout of TIPE2 in the macrophages enhanced the antiviral capacity and facilitated type I interferon (IFN) signaling after RNA viral infection both in vitro and in vivo. Consistently, overexpression of TIPE2 inhibited the production of type I IFNs and pro-inflammatory cytokines, and thus promoted the viral infection. Moreover, TIPE2 restrained the activation of TBK1 and IRF3 in the retinoic acid inducible gene-I (RIG-I)-like receptors (RLR) signaling pathway by directly interacting with retinoic acid inducible gene-I (RIG-I). Taken together, our results suggested that TIPE2 suppresses the type I IFN response induced by RNA virus by targeting RIG-I and blocking the activation of downstream signaling. These findings will provide new insights to reveal the immunological function of TIPE2 and may help to develop new strategies for the clinical treatment of RNA viral infections.
Highlights
Innate immunity constitutes the front line of host immune defense against invading exogenous pathogens by detecting diverse pathogen-associated molecular patterns (PAMPs) through multiple pattern recognition receptors (PRRs) such as retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs) [1,2,3]
We found that vesicular stomatitis virus (VSV) infection downregulated the expression of Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) in macrophages, which implied that TIPE2 may play a role in antiviral innate immunity
We clarified one of the pleiotropic functions of TIPE2, where, it participates in the RIG-I-mediated anti-RNA virus innate immune response, which reveals a new regulatory signaling that serves as a significant composition of host defense against RNA viral infection (Figure 7)
Summary
Innate immunity constitutes the front line of host immune defense against invading exogenous pathogens by detecting diverse pathogen-associated molecular patterns (PAMPs) through multiple pattern recognition receptors (PRRs) such as retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs) [1,2,3]. To induce the antiviral products to jointly elicit antiviral response against invading virus-derived RNA, activated RLR receptors trigger downstream signal transduction to induce the activation of interferon regulatory factor 3/7 (IRF3/7) and result in the production of type I IFNs [4,5,6,7,8]. TIPE2 Negatively Regulates Antiviral Immunity viral clearance, whereas excessive IFNs production may cause tissue damage and spontaneous autoimmunity. Tumor necrosis factor (TNF)-α-induced protein 8-like 2 (TIPE2, known as TNFAIP8L2), one of the four members of the TIPE family, was originally identified as a novel immunoregulatory molecule that negatively regulates T-cell receptor (TCR) and Toll-like receptor (TLR) signal transduction to maintain immune homeostasis [11,12,13]. TIPE2 negatively regulates Poly (I:C) (a double-stranded RNA receptor ligand)-induced anti-RNA immune response by targeting the PI3K-Rac pathway [26]. The physiological role and the underlying mechanism of TIPE2 in antiviral innate immunity are still obscure; rarely reports can be found in this field so far, indicating that better understanding is essential and indispensable
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