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Proteomic elucidation of the targets and primary functions of the picornavirus 2A protease

Picornaviruses are small RNA viruses that hijack host cell machinery to promote their replication. During infection, these viruses express two proteases, 2A(pro) and 3C(pro), which process viral proteins. They also subvert a number of host functions, including innate immune responses, host protein s...

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Autores principales: Serganov, Artem A., Udi, Yael, Stein, Milana E., Patel, Valay, Fridy, Peter C., Rice, Charles M., Saeed, Mohsan, Jacobs, Erica Y., Chait, Brian T., Rout, Michael P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9168619/
https://www.ncbi.nlm.nih.gov/pubmed/35367208
http://dx.doi.org/10.1016/j.jbc.2022.101882
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author Serganov, Artem A.
Udi, Yael
Stein, Milana E.
Patel, Valay
Fridy, Peter C.
Rice, Charles M.
Saeed, Mohsan
Jacobs, Erica Y.
Chait, Brian T.
Rout, Michael P.
author_facet Serganov, Artem A.
Udi, Yael
Stein, Milana E.
Patel, Valay
Fridy, Peter C.
Rice, Charles M.
Saeed, Mohsan
Jacobs, Erica Y.
Chait, Brian T.
Rout, Michael P.
author_sort Serganov, Artem A.
collection PubMed
description Picornaviruses are small RNA viruses that hijack host cell machinery to promote their replication. During infection, these viruses express two proteases, 2A(pro) and 3C(pro), which process viral proteins. They also subvert a number of host functions, including innate immune responses, host protein synthesis, and intracellular transport, by utilizing poorly understood mechanisms for rapidly and specifically targeting critical host proteins. Here, we used proteomic tools to characterize 2A(pro) interacting partners, functions, and targeting mechanisms. Our data indicate that, initially, 2A(pro) primarily targets just two cellular proteins: eukaryotic translation initiation factor eIF4G (a critical component of the protein synthesis machinery) and Nup98 (an essential component of the nuclear pore complex, responsible for nucleocytoplasmic transport). The protease appears to employ two different cleavage mechanisms; it likely interacts with eIF3L, utilizing the eIF3 complex to proteolytically access the eIF4G protein but also directly binds and degrades Nup98. This Nup98 cleavage results in only a marginal effect on nuclear import of proteins, while nuclear export of proteins and mRNAs were more strongly affected. Collectively, our data indicate that 2A(pro) selectively inhibits protein translation, key nuclear export pathways, and cellular mRNA localization early in infection to benefit viral replication at the expense of particular cell functions.
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spelling pubmed-91686192022-06-08 Proteomic elucidation of the targets and primary functions of the picornavirus 2A protease Serganov, Artem A. Udi, Yael Stein, Milana E. Patel, Valay Fridy, Peter C. Rice, Charles M. Saeed, Mohsan Jacobs, Erica Y. Chait, Brian T. Rout, Michael P. J Biol Chem Research Article Picornaviruses are small RNA viruses that hijack host cell machinery to promote their replication. During infection, these viruses express two proteases, 2A(pro) and 3C(pro), which process viral proteins. They also subvert a number of host functions, including innate immune responses, host protein synthesis, and intracellular transport, by utilizing poorly understood mechanisms for rapidly and specifically targeting critical host proteins. Here, we used proteomic tools to characterize 2A(pro) interacting partners, functions, and targeting mechanisms. Our data indicate that, initially, 2A(pro) primarily targets just two cellular proteins: eukaryotic translation initiation factor eIF4G (a critical component of the protein synthesis machinery) and Nup98 (an essential component of the nuclear pore complex, responsible for nucleocytoplasmic transport). The protease appears to employ two different cleavage mechanisms; it likely interacts with eIF3L, utilizing the eIF3 complex to proteolytically access the eIF4G protein but also directly binds and degrades Nup98. This Nup98 cleavage results in only a marginal effect on nuclear import of proteins, while nuclear export of proteins and mRNAs were more strongly affected. Collectively, our data indicate that 2A(pro) selectively inhibits protein translation, key nuclear export pathways, and cellular mRNA localization early in infection to benefit viral replication at the expense of particular cell functions. American Society for Biochemistry and Molecular Biology 2022-03-31 /pmc/articles/PMC9168619/ /pubmed/35367208 http://dx.doi.org/10.1016/j.jbc.2022.101882 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Serganov, Artem A.
Udi, Yael
Stein, Milana E.
Patel, Valay
Fridy, Peter C.
Rice, Charles M.
Saeed, Mohsan
Jacobs, Erica Y.
Chait, Brian T.
Rout, Michael P.
Proteomic elucidation of the targets and primary functions of the picornavirus 2A protease
title Proteomic elucidation of the targets and primary functions of the picornavirus 2A protease
title_full Proteomic elucidation of the targets and primary functions of the picornavirus 2A protease
title_fullStr Proteomic elucidation of the targets and primary functions of the picornavirus 2A protease
title_full_unstemmed Proteomic elucidation of the targets and primary functions of the picornavirus 2A protease
title_short Proteomic elucidation of the targets and primary functions of the picornavirus 2A protease
title_sort proteomic elucidation of the targets and primary functions of the picornavirus 2a protease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9168619/
https://www.ncbi.nlm.nih.gov/pubmed/35367208
http://dx.doi.org/10.1016/j.jbc.2022.101882
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