biostudies-literatureLizcano-Perret BLoterie Nationale (Belgium)Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture (FRIA)Fonds pour la Formation à la Recherche dans l&apos;Industrie et dans l&apos;AgricultureFonds De La Recherche Scientifique - FNRSLoterie Nationalee0127525https://www.ebi.ac.uk/biostudies/studies/S-EPMC12548433biostudies-literatureUnknown99(10)Unrelated pathogens, including viruses and bacteria, use a common short linear motif (SLiM) to interact with cellular kinases of the RSK (p90 S6 ribosomal kinase) family. Such a "DDVF" (D/E-D/E-V-F) SLiM occurs in the leader (L) protein encoded by picornaviruses of the genus <i>Cardiovirus</i>, including Theiler's murine encephalomyelitis virus (TMEV), Boone cardiovirus (BCV), and Encephalomyocarditis virus (EMCV). The L-RSK complex is targeted to the nuclear pore, where RSK triggers FG-nucleoporins hyperphosphorylation, thereby causing nucleocytoplasmic trafficking disruption. In this work, we identified a second SLiM in the L proteins of TMEV and BCV, which enables the L-RSK complex to interact with RAE1 at the level of the nuclear pore complex. AlphaFold predictions suggest that the RAEJournal of virologyThe leader proteins of Theiler's virus and Boone cardiovirus use a combination of short linear motifs (SLiMs) to target RSK kinases to the nuclear pore complex.PMC12548433FellowshipPDR T.0154.23support via de Duve InstituteAspirantEOS IDs 30981113 and 40007527Sorgeloos FDuflos CWavreil FLizcano-Perret BMichiels TVeinstein MMilcamps RfalseThe leader proteins of Theiler's virus and Boone cardiovirus use a combination of short linear motifs (SLiMs) to target RSK kinases to the nuclear pore complex.Unrelated pathogens, including viruses and bacteria, use a common short linear motif (SLiM) to interact with cellular kinases of the RSK (p90 S6 ribosomal kinase) family. Such a "DDVF" (D/E-D/E-V-F) SLiM occurs in the leader (L) protein encoded by picornaviruses of the genus <i>Cardiovirus</i>, including Theiler's murine encephalomyelitis virus (TMEV), Boone cardiovirus (BCV), and Encephalomyocarditis virus (EMCV). The L-RSK complex is targeted to the nuclear pore, where RSK triggers FG-nucleoporins hyperphosphorylation, thereby causing nucleocytoplasmic trafficking disruption. In this work, we identified a second SLiM in the L proteins of TMEV and BCV, which enables the L-RSK complex to interact with RAE1 at the level of the nuclear pore complex. AlphaFold predictions suggest that the RAE2025-01-01T00:00:00Z2025 Oct2026-06-05T04:37:29.691Z2026-05-13T14:28:56.456ZS-EPMC125484334092824910.1128/jvi.01275-25