LAUSR

Significance Successful microbial infections typically involve the subversion of host immune pathways by pathogen-specific virulence factors. Here, we uncovered that viruses and bacteria independently evolved effectors targeting the same conserved loop of the mitogen-activated protein kinase (MAPK) p90-ribosomal S6-kinases (RSKs). Kinase usurpation relies on a previously unidentified short linear motif (SLiM) shared by these virulence factors. Mechanistically, RSK kinase binding prevents its dephosphorylation, thus promoting its phosphorylating activity. Remarkably, while viruses and bacteria evolved an identical mechanism of kinase activation, downstream effect diverged, effectively disarming different arms of the immune system according to their own need. This is a prominent illustration of trans-kingdom convergent evolution across microbial pathogens to usurp key signaling kinases. 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.