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Cardiovirus leader proteins retarget RSK kinases toward alternative substrates to perturb nucleocytoplasmic traffic
Proteins from some unrelated pathogens, including small RNA viruses of the family Picornaviridae, large DNA viruses such as Kaposi sarcoma-associated herpesvirus and even bacteria of the genus Yersinia can recruit cellular p90-ribosomal protein S6 kinases (RSKs) through a common linear motif and mai...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779665/ https://www.ncbi.nlm.nih.gov/pubmed/36508477 http://dx.doi.org/10.1371/journal.ppat.1011042 |
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author | Lizcano-Perret, Belén Lardinois, Cécile Wavreil, Fanny Hauchamps, Philippe Herinckx, Gaëtan Sorgeloos, Frédéric Vertommen, Didier Gatto, Laurent Michiels, Thomas |
author_facet | Lizcano-Perret, Belén Lardinois, Cécile Wavreil, Fanny Hauchamps, Philippe Herinckx, Gaëtan Sorgeloos, Frédéric Vertommen, Didier Gatto, Laurent Michiels, Thomas |
author_sort | Lizcano-Perret, Belén |
collection | PubMed |
description | Proteins from some unrelated pathogens, including small RNA viruses of the family Picornaviridae, large DNA viruses such as Kaposi sarcoma-associated herpesvirus and even bacteria of the genus Yersinia can recruit cellular p90-ribosomal protein S6 kinases (RSKs) through a common linear motif and maintain the kinases in an active state. On the one hand, pathogens’ proteins might hijack RSKs to promote their own phosphorylation (direct target model). On the other hand, some data suggested that pathogens’ proteins might dock the hijacked RSKs toward a third interacting partner, thus redirecting the kinase toward a specific substrate. We explored the second hypothesis using the Cardiovirus leader protein (L) as a paradigm. The L protein is known to trigger nucleocytoplasmic trafficking perturbation, which correlates with hyperphosphorylation of phenylalanine-glycine (FG)-nucleoporins (FG-NUPs) such as NUP98. Using a biotin ligase fused to either RSK or L, we identified FG-NUPs as primary partners of the L-RSK complex in infected cells. An L protein mutated in the central RSK-interaction motif was readily targeted to the nuclear envelope whereas an L protein mutated in the C-terminal domain still interacted with RSK but failed to interact with the nuclear envelope. Thus, L uses distinct motifs to recruit RSK and to dock the L-RSK complex toward the FG-NUPs. Using an analog-sensitive RSK2 mutant kinase, we show that, in infected cells, L can trigger RSK to use NUP98 and NUP214 as direct substrates. Our data therefore illustrate a novel virulence mechanism where pathogens’ proteins hijack and retarget cellular protein kinases toward specific substrates, to promote their replication or to escape immunity. |
format | Online Article Text |
id | pubmed-9779665 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-97796652022-12-23 Cardiovirus leader proteins retarget RSK kinases toward alternative substrates to perturb nucleocytoplasmic traffic Lizcano-Perret, Belén Lardinois, Cécile Wavreil, Fanny Hauchamps, Philippe Herinckx, Gaëtan Sorgeloos, Frédéric Vertommen, Didier Gatto, Laurent Michiels, Thomas PLoS Pathog Research Article Proteins from some unrelated pathogens, including small RNA viruses of the family Picornaviridae, large DNA viruses such as Kaposi sarcoma-associated herpesvirus and even bacteria of the genus Yersinia can recruit cellular p90-ribosomal protein S6 kinases (RSKs) through a common linear motif and maintain the kinases in an active state. On the one hand, pathogens’ proteins might hijack RSKs to promote their own phosphorylation (direct target model). On the other hand, some data suggested that pathogens’ proteins might dock the hijacked RSKs toward a third interacting partner, thus redirecting the kinase toward a specific substrate. We explored the second hypothesis using the Cardiovirus leader protein (L) as a paradigm. The L protein is known to trigger nucleocytoplasmic trafficking perturbation, which correlates with hyperphosphorylation of phenylalanine-glycine (FG)-nucleoporins (FG-NUPs) such as NUP98. Using a biotin ligase fused to either RSK or L, we identified FG-NUPs as primary partners of the L-RSK complex in infected cells. An L protein mutated in the central RSK-interaction motif was readily targeted to the nuclear envelope whereas an L protein mutated in the C-terminal domain still interacted with RSK but failed to interact with the nuclear envelope. Thus, L uses distinct motifs to recruit RSK and to dock the L-RSK complex toward the FG-NUPs. Using an analog-sensitive RSK2 mutant kinase, we show that, in infected cells, L can trigger RSK to use NUP98 and NUP214 as direct substrates. Our data therefore illustrate a novel virulence mechanism where pathogens’ proteins hijack and retarget cellular protein kinases toward specific substrates, to promote their replication or to escape immunity. Public Library of Science 2022-12-12 /pmc/articles/PMC9779665/ /pubmed/36508477 http://dx.doi.org/10.1371/journal.ppat.1011042 Text en © 2022 Lizcano-Perret et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Lizcano-Perret, Belén Lardinois, Cécile Wavreil, Fanny Hauchamps, Philippe Herinckx, Gaëtan Sorgeloos, Frédéric Vertommen, Didier Gatto, Laurent Michiels, Thomas Cardiovirus leader proteins retarget RSK kinases toward alternative substrates to perturb nucleocytoplasmic traffic |
title | Cardiovirus leader proteins retarget RSK kinases toward alternative substrates to perturb nucleocytoplasmic traffic |
title_full | Cardiovirus leader proteins retarget RSK kinases toward alternative substrates to perturb nucleocytoplasmic traffic |
title_fullStr | Cardiovirus leader proteins retarget RSK kinases toward alternative substrates to perturb nucleocytoplasmic traffic |
title_full_unstemmed | Cardiovirus leader proteins retarget RSK kinases toward alternative substrates to perturb nucleocytoplasmic traffic |
title_short | Cardiovirus leader proteins retarget RSK kinases toward alternative substrates to perturb nucleocytoplasmic traffic |
title_sort | cardiovirus leader proteins retarget rsk kinases toward alternative substrates to perturb nucleocytoplasmic traffic |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9779665/ https://www.ncbi.nlm.nih.gov/pubmed/36508477 http://dx.doi.org/10.1371/journal.ppat.1011042 |
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