Cytosolic and nuclear recognition of virus and viral evasion

Abstract

The innate immune system is the first line of host defense, which responds rapidly to viral infection. Innate recognition of viruses is mediated by a set of pattern recognition receptors (PRRs) that sense viral genomic nucleic acids and/or replication intermediates. PRRs are mainly localized either to the endosomes, the plasma membrane or the cytoplasm. Recent evidence suggested that several proteins located in the nucleus could also act as viral sensors. In turn, these important elements are becoming the target for most viruses to evade host immune surveillance. In this review, we focus on the recent progress in the study of viral recognition and evasion.

Keywords: DNA sensor; Innate immunity; RNA sensor; Viral evasion.

Fig. 1

Cytosolic viral RNA sensing. The RLR family members MDA5 and RIG-I preferentially recognize long dsRNA and 5′- triphosphate short dsRNA, respectively. RIG-I can also recognize circular RNA synthesized in vitro and derived from virus. After RNA ligand binding, RIG-I and MDA5 undergo conformational changes that expose N-terminal CARDs to mediate downstream signaling. Riplet/TRIM25 or TRIM65-mediated K63-linked ubiquitination induces RIG-I and MDA5 activation, respectively. Both RIG-I and MDA5 can interact with MAVS on the outer membrane of mitochondria and activate MAVS to form signal platform, which further activates NFκB via the IKK complex or IRF3 via TBK1. DHX58 is reported to facilitate MDA5 activation, whereas it drives the inactivation of RIG-I. Besides, DDX1-DDX21-DHX36 complex recognizes viral dsRNA and activates TRIF pathway. DDX19A senses viral RNA and activates NLRP3 inflammasome. DHX33 senses cytosolic viral dsRNA and interacts with MAVS to activate innate immune signaling. DDX60 is needed for the activation of RIG-I by binding to viral RNA. ADAR1 recognizes viral dsRNA suppresses dsRNA-induced signaling. LRRFIP1 recognizes dsRNA and L. monocytogenes dsDNA. Moreover, IFIT1 and IFIT5 can recognize 5′- triphosphate ssRNA

Fig. 2

Cytosolic viral DNA sensing. DNA is a PAMP that can be delivered to the cytoplasm of host cells during microbial infection. Several DNA sensors have been reported to promote the activation of innate immune signaling by activating a STING-dependent signaling pathway. Among them, cGAS can catalyze ATP and GTP to generate the second messenger cyclic GMP-AMP (cGAMP) and then activate STING. However, the molecular basis by which other DNA sensors activate STING is not well understood. RNA polymerase III can activate the immune response in a STING-independent way, RNA polymerase III can transcribe poly (dA-dT) into dsRNA, which is then recognized by RIG-I. Several members of DExD/H helicases are also respond to cytosolic dsDNA, such as DHX9, DHX36 and DDX41. In IRF3-mediated innate immune responses of fibroblasts, DNA-PK recognizes cytoplasmic dsDNA of vaccinia virus. TREX1 is well known to protect host from excessive inflammation via efficiently degrading cytosolic endogenous DNA. PYHIN family proteins: AIM2 and IFI16. AIM2 senses dsDNA from virus and oligomerizes to form AIM2 inflammasome. IFI16 binds to cytoplasmic viral DNA and mediates the activation of STING-TBK1-IRF3 axis. Moreover, NLRC3 recognizes dsDNA and releases STING, which activates type I interferon induction

Fig. 3

Innate immune evasion strategies of targeting RLR signaling pathway. Viruses can escape from host immune clearance. For example, DENV can replicate in endoplasmic reticulum to efficiently hide dsRNA from the cytoplasm. BDV encodes phosphatases to process the 5′-ppp on its genome to 5′-p. The protein viral protein 35 (VP35) of EBOV can interact with dsRNA to prevent dsRNA from being detected by RLRs. Moreover, RLR signaling can be inhibited by viral proteins that either directly bind MDA5, RIG-I, MAVS, TBK1 to inhibit their function or induce their degradation

Fig. 4

Innate immune evasion strategies of targeting DNA signaling pathway. DNA signaling can be restrained by viral proteins that either interact with IFI16, cGAS, DNA-PK or STING directly or cause their degradation