A case of convergent evolution: Several viral and bacterial pathogens hijack RSK kinases through a common linear motif

Abstract

Microbes have been coevolving with their host for millions of years, exploiting host resources to their own benefit. We show that viral and bacterial pathogens convergently evolved to hijack cellular mitogen-activated protein kinase (MAPK) p90-ribosomal S6-kinases (RSKs). Theiler’s virus leader (L) protein binds RSKs and prevents their dephosphorylation, thus maintaining the kinases active. Recruitment of RSKs enables L-protein-mediated inhibition of eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2 or PKR) and stress granule formation. Strikingly, ORF45 protein of Kaposi’s sarcoma-associated herpesvirus (KSHV) and YopM protein of Yersinia use the same peptide motif as L to recruit and activate RSKs. All three proteins interact with a conserved surface-located loop of RSKs, likely acting as an allosteric regulation site. Some unrelated viruses and bacteria thus evolved to harness RSKs in a common fashion, yet to target distinct aspects of innate immunity. As documented for Varicella zoster virus ORF11, additional pathogens likely evolved to hijack RSKs, using a similar short linear motif.

Proteolytic Activities of Enterovirus 2A Do Not Depend on Its Interaction with SETD3

“…The Nup phosphorylation triggered by L protein is mediated by mitogen-activated protein kinases [ 44 ]. Recently, the Leader protein was shown to interact with mitogen-activated protein kinase p90-ribosomal S6-kinases (RSKs) and prevent their dephosphorylation, thereby maintaining the activity of kinases [ 45 ]. Whether 2A pro also affects the activity of some kinases and thereby triggers Nup phosphorylation or, alternatively, whether it triggers NCTD through another mechanism requires further investigation.…”

Cardiovirus leader proteins retarget RSK kinases toward alternative substrates to perturb nucleocytoplasmic traffic

“…Proteins encoded by several unrelated pathogens, including RNA viruses, DNA viruses and bacteria, were recently shown to use a common short linear motif (D/E-D/E-V-F, referred to as DDVF hereafter) to recruit members of the cellular p90-ribosomal S6 protein kinases (RSKs) family: RSK1, RSK2, RSK3 and RSK4 (Sorgeloos et al, 2022, Alexa et al, 2022). Interestingly, competition and cross-linking experiments, as well as crystallography data show that these pathogens’ proteins, the leader (L) protein (cardioviruses), ORF45 (Kaposi sarcoma-associated herpes virus - KSHV) and YopM ( Yersinia ) use a common interface to recruit RSKs.…”

“…Interestingly, competition and cross-linking experiments, as well as crystallography data show that these pathogens’ proteins, the leader (L) protein (cardioviruses), ORF45 (Kaposi sarcoma-associated herpes virus - KSHV) and YopM ( Yersinia ) use a common interface to recruit RSKs. Binding of the pathogens’ proteins prevents RSK dephosphorylation by cellular phosphatases, thereby maintaining RSK in an active state (Sorgeloos et al, 2022, Alexa et al, 2022). Although infection with all three pathogens leads to RSK activation, the outcome of this activation differs according to the protein bound to RSK.…”

“…Although infection with all three pathogens leads to RSK activation, the outcome of this activation differs according to the protein bound to RSK. YopM association with RSK was proposed to inhibit the inflammasome and to lead to IL-10 production (Chung et al, 2016, Ratner et al, 2016); RSK recruitment by ORF45 enhances lytic replication of KSHV (Kuang et al, 2011, Li et al, 2015), whereas RSK recruitment by cardiovirus L protein leads to the inhibition of the antiviral eukaryotic initiation factor 2 alpha kinase 2 (EIF2AK2), better known as PKR (Sorgeloos et al, 2022). PKR inhibition by L was shown to depend on L interaction with RSK but also on L protein’s C-terminal domain.…”

“…the C-terminal domain for L), they recruit proteins that could serve as substrate for RSKs. After phosphorylation, such proteins would act as effectors to the benefit of the pathogen (Figure 1A) (Sorgeloos et al, 2022). In an alternative model, proteins interacting with RSK through the conserved DDVF motif could directly act as preferential substrates for RSK-mediated phosphorylation (Figure 1B), as was suggested for protein RHBDF1 (Rhomboid 5 homolog 1) (Alexa et al, 2022).…”