Interplay Between CMGC Kinases Targeting SR Proteins and Viral Replication: Splicing and Beyond.

Florentin Pastor,Benoit Chabot,Anna Salvetti,David Durantel,Lulzim Shkreta

doi:10.3389/fmicb.2021.658721

Abstract

Protein phosphorylation constitutes a major post-translational modification that critically regulates the half-life, intra-cellular distribution, and activity of proteins. Among the large number of kinases that compose the human kinome tree, those targeting RNA-binding proteins, in particular serine/arginine-rich (SR) proteins, play a major role in the regulation of gene expression by controlling constitutive and alternative splicing. In humans, these kinases belong to the CMGC [Cyclin-dependent kinases (CDKs), Mitogen-activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and Cdc2-like kinases (CLKs)] group and several studies indicate that they also control viral replication via direct or indirect mechanisms. The aim of this review is to describe known and emerging activities of CMGC kinases that share the common property to phosphorylate SR proteins, as well as their interplay with different families of viruses, in order to advance toward a comprehensive knowledge of their pro- or anti-viral phenotype and better assess possible translational opportunities.

Highlights

Cellular RNA binding proteins (RBPs) form a large and continuously expanding family of proteins that play fundamental roles at all steps of RNA metabolism, including transcription, splicing, transport, stability, and translation (Hentze et al, 2018)
Several kinases have been reported to phosphorylate SR proteins. All these kinases belong to the CMGC [Cyclin-dependent kinases (CDKs), Mitogen-activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and Cdc2-like kinases (CLKs)] group that includes eight families of highly inter-connected kinases that regulate a variety of processes and, in particular, transcription and RNA processing (Varjosalo et al, 2013; Figure 3)
This study suggests that a kinase involved in SR proteins phosphorylation may controls the Hepatitis B virus (HBV) life cycle at an intra-nuclear step by targeting SRSF10 and potentially other SR proteins associated to Core

Summary

Introduction

Cellular RNA binding proteins (RBPs) form a large and continuously expanding family of proteins that play fundamental roles at all steps of RNA metabolism, including transcription, splicing, transport, stability, and translation (Hentze et al, 2018). Among RBPs, serine/ arginine-rich (SR) proteins constitute a conserved family of 12 proteins in humans that were initially discovered as factors required for constitutive and capable of regulating alternative splicing (AS; Long and Caceres, 2009; Howard and Sanford, 2015) In addition to their roles in initiating spliceosome assembly and helping define 5' and 3' splice sites, subsequent studies showed that besides their role in splicing, SR proteins, as other RBPs, have multiple additional functions in mRNA metabolism, including transcription, regulation of export of spliced mRNA from the nucleus, stabilization of cytoplasmic transcripts, and promotion of mRNA translation by ribosomes (Figure 1; see Anko, 2014 for a review). As other membraneless nuclear bodies, speckles are formed by proteins, DNA and RNA components that condensate through a process of liquid-liquid phase separation and that can reversibly dissociate upon external stimuli or during the cell cycle (Strom and Brangwynne, 2019; Greig et al, 2020)

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