The Leader protein of Cardioviruses hijacks cellular protein kinases via an evolutionary convergent mechanism to trigger host protein shut-off and to escape innate immune responses
(2018)
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- Authors
- Supervisors
- Michiels, Thomas
- Abstract
- Theiler’s murine encephalomyelitis virus (TMEV) belongs to the Cardiovirus genus, in the Picornaviridae family. As other Cardioviruses, it expresses a small accessory protein, called Leader (L), which is implicated in escaping host immune response. The L protein was shown to induce a global translational shut-off, to disrupt nucleocytoplasmic trafficking of mRNAs and proteins, to block the formation of stress granules by impeding the activation of double-stranded RNA-dependent protein kinase, to block the production of type I interferon, and to modulate apoptosis. In addition, it was found to hijack cellular protein kinases of the p90 ribosomal S6 kinase (RSK) family by recruiting them and inhibiting their dephosphorylation by phosphatases, thereby leading to their sustained hyperactivation. Strikingly, two other very different pathogens, Kaposi’s sarcoma-associated herpes virus and bacteria of the genus Yersinia, express proteins (ORF45 and YopM, respectively) that interact with and activate RSKs exactly as the L protein does. This work aimed at understanding the mechanism of RSK activation by the L protein and at exploring the role of RSK activation in TMEV replication and L activities. We thus defined the interface between the pathogens’ proteins and the protein kinases in order to understand the basis of RSK activation. By mutagenesis, co-immunoprecipitation and cross-linking experiments, we identified the amino acids involved in the interface between L and RSK. Very interestingly, all three pathogens’ proteins (L, ORF45 and YopM) interact with RSKs thanks to a common consensus motif. Moreover, they interact with the same RSK residues, in a motif that is extraordinarily conserved across species and thus likely important to regulate kinase activity. In fine, this part of work allowed us to highlight a yet unknown evolutionary convergence of at least three very different pathogens (RNA virus, DNA virus and bacteria) to hijack RSKs. Next, we evaluated how RSKs are implicated in TMEV replication. Unfortunately, we were not able to reach a clear conclusion even if replication likely depends on the expressed RSK isoform. Finally, the functional relevance of RSK activation was tested regarding L functions. We found that L (but not ORF45 and YopM) induced a RSK-mediated protein synthesis shut-off. Likewise, work performed by other members of the laboratory reported other distinct consequences of RSK activation for L, ORF45 and YopM. Taken together, these data suggest a model where three pathogens’ proteins recruit and activate RSKs for different purposes.
- Affiliations
Citations
Peeters, M. (2018). The Leader protein of Cardioviruses hijacks cellular protein kinases via an evolutionary convergent mechanism to trigger host protein shut-off and to escape innate immune responses. https://hdl.handle.net/2078.5/40205