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

Proteins from unrelated pathogens, including some RNA or DNA viruses and bacteria can recruit and activate cellular p90-ribosomal protein S6 kinases (RSKs) through a common linear motif. Data suggested a model where pathogens' proteins act to dock the recruited RSKs toward specific substrates, which then act as effectors to the benefit of the pathogens. Using cardiovirus leader protein (L) as a paradigm, we show that pathogens' proteins can modify the spectrum of RSK substrates in infected cells. L triggers nucleocytoplasmic trafficking perturbation and phenylalanine-glycine (FG)-nucleoporin hyperphosphorylation in an RSK-dependent fashion. Biotin ligase experiments identified FG-nucleoporins as common partners of L and RSK in infected cells. Using cells expressing an analog-sensitive RSK2 mutant, we show that L triggers direct phosphorylation of NUP98 and NUP214 by RSK2 in infected cells. Our data therefore demonstrate a novel virulence mechanism where pathogens' proteins hijack and retarget cellular protein kinases of the RSK family