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

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.

The Omnipresence of DYRK1A in Human Diseases

“…The ability of viruses to hijack the cellular machinery makes them strategic players in the development of human diseases [ 68 , 124 ]. Several studies have demonstrated interactions between viruses and kinases from the CMGC group.…”

“…Hence, viruses appear to be able to co-opt these kinases to optimize their replication in the cell and the action of some kinases appears to inhibit viral activity. Within this context, DYRK1A is of significant interest [ 124 ]. Indeed, this enzyme phosphorylates SR proteins ( Table 1 ) which play major roles in the regulation of gene expression by controlling constitutive and alternative splicing and thus viral expression.…”

“…Indeed, this enzyme phosphorylates SR proteins ( Table 1 ) which play major roles in the regulation of gene expression by controlling constitutive and alternative splicing and thus viral expression. In the context of HIV-1t, DYRK1A regulates the activity of several transcription factors like NFAT and cyclin L2 ( Table 1 ) thus making viruses latent and preventing replication in macrophages [ 68 , 124 , 125 ]. Moreover, DYRK1A interacts also with oncoproteins from adenovirus and human papillomavirus (HPV) [ 52 , 126 ].…”

Good Cop, Bad Cop: The Different Roles of SRPKs

“…The nuclear fraction of SRPKs, in collaboration with CLKs, adjusts the degree of phosphorylation of SR proteins and thus modulates the splicing pattern of several genes. ( Stamm, 2008 ; Aubol et al, 2016 ; Naro et al, 2021 ; Pastor et al, 2021 ). Furthermore, it may also regulate other nuclear processes via the phosphorylation of additional nuclear substrates (see below).…”

Insights into the mechanism of pre-mRNA splicing of tiny introns from the genome of a giant ciliate Stentor coeruleus

“…Intriguingly, we observed that while orthologs of heterogeneous nuclear ribonucleoproteins (hnRNPs) were identified, all Serine/Arginine (SR)-rich splicing factors and SR-related proteins were absolutely absent from our search results. Both hnRNPs and SR-family proteins function as general splicing repressors and activators, respectively [19][20][21][22] . Mechanistically, they interact with cis-elements in the transcripts and then recruit and/or stabilize components of the core spliceosome 21,23 .…”