Role of MAPK/MNK1 signaling in virus replication

Abstract

Viruses are obligate intracellular parasites; they heavily depend on the host cell machinery to effectively replicate and produce new progeny virus particles. Following viral infection, diverse cell signaling pathways are initiated by the cells, with the major goal of establishing an antiviral state. However, viruses have been shown to exploit cellular signaling pathways for their own effective replication. Genome-wide siRNA screens have also identified numerous host factors that either support (proviral) or inhibit (antiviral) virus replication. Some of the host factors might be dispensable for the host but may be critical for virus replication; therefore such cellular factors may serve as targets for development of antiviral therapeutics. Mitogen activated protein kinase (MAPK) is a major cell signaling pathway that is known to be activated by diverse group of viruses. MAPK interacting kinase 1 (MNK1) has been shown to regulate both cap-dependent and internal ribosomal entry sites (IRES)-mediated mRNA translation. In this review we have discuss the role of MAPK in virus replication, particularly the role of MNK1 in replication and translation of viral genome.

Keywords: Antiviral drugs; MAPK; MNK1; Signaling pathway; Virus replication.

Fig. 1

MAPK/MNK signaling. MAPK/MNK signaling pathway is activated by binding of the ligands to their cognate receptors (RTKs/GPCRs). In RTKs, ligand binding induces dimerization and autophosphorylation at its Ser/Thr residues (intracytoplasmic domain). With the help of adaptor proteins- SOS/Grb2, activated RTKs convert Ras-GDP to Ras-GTP. In GPCRs, ligand binding induces structural changes in heterotrimeric subunits. These structural changes trigger generation of secondary messenger, which eventually converts Ras-GDP to Ras-GTP. Upon formation of Ras-GTP, further information in the pathway is conveyed by three sequentially acting evolutionary conserved proteins of MAPK-ERK family namely Raf (MAPKKKs), MEK1/2 (MAPKKs) and ERK1/2 (MAPK). Besides ERK signaling, Ras-GTP also activates those MAPKKKs, which are required for phosphorylation of MEK4/7 and MEK3/6 to trigger JNK and p38 pathway respectively. The ERK1/2 and p38 activation ultimately results in phosphorylation of MNK1. Activated MNK1 regulates functions of several potential downstream substrates. eIF4E and eIF4 G, which help in formation of 5′ cap-dependent mRNA translation initiation complex (eIF4 F). hnRNPA1 helps in pre-mRNA processing. PSF involves in post translational processing as well as translocation of mRNA. cPLA2, which regulates production of eicosanoids, a second messenger, plays an important role in immunity and inflammation. Spry2 is associated with interferon production and negative regulation of ERK/MAPK pathway. Besides, MNK1 also participates in regulation of cap-independent mRNA translation, which involves activation of SRPK, mediated via mTOR. By activating transcriptional factors such as c-Jun, c-Fos STAT1, ATF1/2/6, Elk1, Ets1, p53 and NF-κB, JNK and p38 induce inflammatory response.

Fig. 2

Role of MNK1 in viral mRNA translation. MAPK pathway is activated by binding of the ligands to their cognate receptors (RTKs/GPCRs). With the help of adaptor proteins (SOS/Grb2), activated receptors convert Ras-GDP to Ras-GTP. Further information in the pathway is conveyed by phosphorylation (activation) of a series of enzymes, namely Raf, MEK1/2, and ERK1/2 which leads to activation of MNK1. Alternatively, MNK1 may be acitivated by p38. Besides regulating cell proliferation, cell survival and immune response, activated MNK1 also regulates viral mRNA translation. Activated MNK1 leads to dissociation of 4EBP1-eIF4E complex, which results in release (mediated via mTORC1) and subsequently phosphorylation of eIF4E. Activated eIF4E is required for assembly of eIF4 F to initiate cap-dependent viral mRNA translation. Alternatively, MNK1 may modulate SRPK function by directly inhibiting mTORC2-Akt signaling which is prerequisite for cell survival during viral infection. Activated SRPK phosphorylates SRPs that bind with IRES in the viral genome to initiate cap-independent viral mRNA translation. Activated MNK1 also facilitates pre-mRNA and post-translational processing, mediated via hnRNPA1 and PSF respectively.