Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Lizcano-Perret, Belén, Lardinois, Cécile, Wavreil, Fanny, Hauchamps, Philippe, Herinckx, Gaëtan, Sorgeloos, Frédéric, Vertommen, Didier, Gatto, Laurent, Michiels, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
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
_version_ 1784856665265274880
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
work_keys_str_mv AT lizcanoperretbelen cardiovirusleaderproteinsretargetrskkinasestowardalternativesubstratestoperturbnucleocytoplasmictraffic
AT lardinoiscecile cardiovirusleaderproteinsretargetrskkinasestowardalternativesubstratestoperturbnucleocytoplasmictraffic
AT wavreilfanny cardiovirusleaderproteinsretargetrskkinasestowardalternativesubstratestoperturbnucleocytoplasmictraffic
AT hauchampsphilippe cardiovirusleaderproteinsretargetrskkinasestowardalternativesubstratestoperturbnucleocytoplasmictraffic
AT herinckxgaetan cardiovirusleaderproteinsretargetrskkinasestowardalternativesubstratestoperturbnucleocytoplasmictraffic
AT sorgeloosfrederic cardiovirusleaderproteinsretargetrskkinasestowardalternativesubstratestoperturbnucleocytoplasmictraffic
AT vertommendidier cardiovirusleaderproteinsretargetrskkinasestowardalternativesubstratestoperturbnucleocytoplasmictraffic
AT gattolaurent cardiovirusleaderproteinsretargetrskkinasestowardalternativesubstratestoperturbnucleocytoplasmictraffic
AT michielsthomas cardiovirusleaderproteinsretargetrskkinasestowardalternativesubstratestoperturbnucleocytoplasmictraffic