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

Abstract

SummaryProteins 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.