Post‐translational regulation of antiviral innate signaling

Abstract

The innate immune system initiates immune responses by pattern-recognition receptors (PRR). Virus-derived nucleic acids are sensed by the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family and the toll-like receptor (TLR) family as well as the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). These receptors activate IRF3/7 and NF-κB signaling pathways to induce the expression of type I interferons (IFNs) and other cytokines firing antiviral responses within the cell. However, to achieve a favorable outcome for the host, a balanced production of IFNs and activation of antiviral responses is required. Posttranslational modifications (PTMs), such as the covalent linkage of functional groups to amino acid chains, are crucial for this immune homeostasis in antiviral responses. Canonical PTMs including phosphorylation and ubiquitination have been extensively studied and other PTMs such as methylation, acetylation, SUMOylation, ADP-ribosylation and glutamylation are being increasingly implicated in antiviral innate immunity. Here we summarize our recent understanding of the most important PTMs regulating the antiviral innate immune response, and their role in virus-related immune pathogenesis.Keywords: Antiviral immunity r Interferons r Phosphorylation r Post-translational modifications r PRR r Ubiquitination IntroductionInfectious diseases, especially virus infections, are still a serious threat to humanity and the host innate immune system represents a critical defense against invading viruses. Host cells can initiate these innate immune responses by detecting viral DNA and RNA with a set of pattern recognition receptors (PRRs) including the toll-like receptor (TLR) family and the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family, as well as cytosolic DNA sensors such as cyclic GMP-AMP (cGAMP) synthase (cGAS), IFI16 and DDX41 [1,2]. After recognition of viral nucleic acids, these PRRs trigger the production of proinflammatory cytokines, chemokines and type I interferons (IFNs), which subsequently induce synthesis of antiviral proteins, death of infected cells and activation of the adaptive immune response [3,4]. These antiviral signals Correspondence: Dr. Baoxue Ge e-mail: gebaoxue@sibs.ac.cn must be spatially and temporally orchestrated to achieve an optimal outcome for the host and much attention has been raised to understanding the signaling pathways and regulatory factors in the antiviral innate immunity.Toll-like receptors, including TLR3, TLR7, TLR8 and TLR9, sense endosomal nucleic acids derived from the enclosed microbes and infected apoptotic cells. While TLR9 detects unmethylated CpG DNA species, TLR3 and TLR7/8 recognize double-stranded RNA (dsRNA) and single-stranded RNA (ssRNA), respectively [5] ( Fig. 1). Following ligand binding, the TLRs form a signaling platform in which distinct Toll/interleukin-1 receptor (TIR) domaincontaining adaptors are engaged. For instance, TLR3 signals via TIR-domain-containing adaptor protein inducing interferon beta (TRIF), and TLR7/8/9 rel...

ATP1B3 cooperates with BST‐2 to promote hepatitis B virus restriction

“…and IFN production has been provided. 35 Type-I to -III IFNs are known to act as key effectors in the innate immune response against HBV infection. Moreover, IFN-α treatment is licensed for hepatitis B therapy and has resulted in virus clearance in some patients.…”

The Class IV human deacetylase, HDAC11, exhibits anti‐influenza A virus properties via its involvement in host innate antiviral response

“…However, a variety of non-histone proteins, both cytoplasmic and nuclear, are now known to be HDAC substrates (Seto & Yoshida, 2014). HDACs work in equilibrium with histone acetyl transferases to control the acetylation level of proteins and influence diverse biological processes such as gene expression (Sterner & Berger, 2000), protein trafficking (Li & Yang, 2015), and the innate immune response (Zhou, He, Wang, & Ge, 2017). Consequently, the imbalance in protein acetylation due to aberrant function of HDACs or histone acetyl transferases contributes to multiple human diseases such as cancer (Liu, Li, Wu, & Cho, 2017), neurodegeneration (Cook, Stankowski, Carlomagno, Stetler, & Petrucelli, 2014), and infection (Jeng, Ali, & Ott, 2015;Song & Walley, 2016).…”

Virus-Like Particles as an Instrument of Vaccine Production

“…Another goal of nucleic acid packaging into a particle lies in the presentation of viral nucleic acids leading to the activation of specific immune receptors which induce the synthesis of type I interferons (INF) and other cytokines triggering the antivirus response [49]. It has been demonstrated that long DNA and RNA molecules may be incorporated into VLPs.…”

“…Posttranslational protein modifications and covalent bonds between the modifying molecules and the functional groups in the polypeptide chains are of great importance for immune homeostasis during the antiviral response. The balance between phosphorylation, ubiquitination, methylation, acetylation, SUMOylation, ADP-ribosylation, and glutamilation of a certain antigen performs the fine adjustment of the host's antiviral response [49,58]. The structural proteins for VLP production when synthesized in the eukaryotic expression systems undergo a number of posttranslational modifications.…”