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Control of the negative IRES trans-acting factor KHSRP by ubiquitination

Cells and viruses can utilize internal ribosome entry sites (IRES) to drive translation when cap-dependent translation is inhibited by stress or viral factors. IRES trans-acting factors (ITAFs) are known to participate in such cap-independent translation, but there are gaps in the understanding as t...

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Autores principales: Kung, Yu-An, Hung, Chuan-Tien, Chien, Kun-Yi, Shih, Shin-Ru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224474/
https://www.ncbi.nlm.nih.gov/pubmed/27899653
http://dx.doi.org/10.1093/nar/gkw1042
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author Kung, Yu-An
Hung, Chuan-Tien
Chien, Kun-Yi
Shih, Shin-Ru
author_facet Kung, Yu-An
Hung, Chuan-Tien
Chien, Kun-Yi
Shih, Shin-Ru
author_sort Kung, Yu-An
collection PubMed
description Cells and viruses can utilize internal ribosome entry sites (IRES) to drive translation when cap-dependent translation is inhibited by stress or viral factors. IRES trans-acting factors (ITAFs) are known to participate in such cap-independent translation, but there are gaps in the understanding as to how ITAFs, particularly negative ITAFs, regulate IRES-driven translation. This study found that Lys109, Lys121 and Lys122 represent critical ubiquitination sites for far upstream element-binding protein 2 (KHSRP, also known as KH-type splicing regulatory protein or FBP2), a negative ITAF. Mutations at these sites subsequently reduced KHSRP ubiquitination and abolished its inhibitory effect on IRES-driven translation. We further found that interaction between the Kelch domain of Kelch-like protein 12 (KLHL12) and the C-terminal domain of KHSRP contributed to KHSRP ubiquitination, leading to downregulation of enterovirus IRES-mediated translation in infected cells and increased competition against other positive ITAFs. Together, these results show that ubiquitination can exert control over IRES-driven translation via modification of ITAFs, and to the best of our knowledge, this is the first description of such a regulatory mechanism for IRES-dependent translation.
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spelling pubmed-52244742017-01-17 Control of the negative IRES trans-acting factor KHSRP by ubiquitination Kung, Yu-An Hung, Chuan-Tien Chien, Kun-Yi Shih, Shin-Ru Nucleic Acids Res Molecular Biology Cells and viruses can utilize internal ribosome entry sites (IRES) to drive translation when cap-dependent translation is inhibited by stress or viral factors. IRES trans-acting factors (ITAFs) are known to participate in such cap-independent translation, but there are gaps in the understanding as to how ITAFs, particularly negative ITAFs, regulate IRES-driven translation. This study found that Lys109, Lys121 and Lys122 represent critical ubiquitination sites for far upstream element-binding protein 2 (KHSRP, also known as KH-type splicing regulatory protein or FBP2), a negative ITAF. Mutations at these sites subsequently reduced KHSRP ubiquitination and abolished its inhibitory effect on IRES-driven translation. We further found that interaction between the Kelch domain of Kelch-like protein 12 (KLHL12) and the C-terminal domain of KHSRP contributed to KHSRP ubiquitination, leading to downregulation of enterovirus IRES-mediated translation in infected cells and increased competition against other positive ITAFs. Together, these results show that ubiquitination can exert control over IRES-driven translation via modification of ITAFs, and to the best of our knowledge, this is the first description of such a regulatory mechanism for IRES-dependent translation. Oxford University Press 2017-01-09 2016-11-28 /pmc/articles/PMC5224474/ /pubmed/27899653 http://dx.doi.org/10.1093/nar/gkw1042 Text en © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Molecular Biology
Kung, Yu-An
Hung, Chuan-Tien
Chien, Kun-Yi
Shih, Shin-Ru
Control of the negative IRES trans-acting factor KHSRP by ubiquitination
title Control of the negative IRES trans-acting factor KHSRP by ubiquitination
title_full Control of the negative IRES trans-acting factor KHSRP by ubiquitination
title_fullStr Control of the negative IRES trans-acting factor KHSRP by ubiquitination
title_full_unstemmed Control of the negative IRES trans-acting factor KHSRP by ubiquitination
title_short Control of the negative IRES trans-acting factor KHSRP by ubiquitination
title_sort control of the negative ires trans-acting factor khsrp by ubiquitination
topic Molecular Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224474/
https://www.ncbi.nlm.nih.gov/pubmed/27899653
http://dx.doi.org/10.1093/nar/gkw1042
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