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Loss of Trabid, a New Negative Regulator of the Drosophila Immune-Deficiency Pathway at the Level of TAK1, Reduces Life Span

A relatively unexplored nexus in Drosophila Immune deficiency (IMD) pathway is TGF-beta Activating Kinase 1 (TAK1), which triggers both immunity and apoptosis. In a cell culture screen, we identified that Lysine at position 142 was a K63-linked Ubiquitin acceptor site for TAK1, required for signalli...

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Autores principales: Fernando, Merennege Dilan Anush, Kounatidis, Ilias, Ligoxygakis, Petros
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930493/
https://www.ncbi.nlm.nih.gov/pubmed/24586180
http://dx.doi.org/10.1371/journal.pgen.1004117
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author Fernando, Merennege Dilan Anush
Kounatidis, Ilias
Ligoxygakis, Petros
author_facet Fernando, Merennege Dilan Anush
Kounatidis, Ilias
Ligoxygakis, Petros
author_sort Fernando, Merennege Dilan Anush
collection PubMed
description A relatively unexplored nexus in Drosophila Immune deficiency (IMD) pathway is TGF-beta Activating Kinase 1 (TAK1), which triggers both immunity and apoptosis. In a cell culture screen, we identified that Lysine at position 142 was a K63-linked Ubiquitin acceptor site for TAK1, required for signalling. Moreover, Lysine at position 156 functioned as a K48-linked Ubiquitin acceptor site, also necessary for TAK1 activity. The deubiquitinase Trabid interacted with TAK1, reducing immune signalling output and K63-linked ubiquitination. The three tandem Npl4 Zinc Fingers and the catalytic Cysteine at position 518 were required for Trabid activity. Flies deficient for Trabid had a reduced life span due to chronic activation of IMD both systemically as well as in their gut where homeostasis was disrupted. The TAK1-associated Binding Protein 2 (TAB2) was linked with the TAK1-Trabid interaction through its Zinc finger domain that pacified the TAK1 signal. These results indicate an elaborate and multi-tiered mechanism for regulating TAK1 activity and modulating its immune signal.
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spelling pubmed-39304932014-02-25 Loss of Trabid, a New Negative Regulator of the Drosophila Immune-Deficiency Pathway at the Level of TAK1, Reduces Life Span Fernando, Merennege Dilan Anush Kounatidis, Ilias Ligoxygakis, Petros PLoS Genet Research Article A relatively unexplored nexus in Drosophila Immune deficiency (IMD) pathway is TGF-beta Activating Kinase 1 (TAK1), which triggers both immunity and apoptosis. In a cell culture screen, we identified that Lysine at position 142 was a K63-linked Ubiquitin acceptor site for TAK1, required for signalling. Moreover, Lysine at position 156 functioned as a K48-linked Ubiquitin acceptor site, also necessary for TAK1 activity. The deubiquitinase Trabid interacted with TAK1, reducing immune signalling output and K63-linked ubiquitination. The three tandem Npl4 Zinc Fingers and the catalytic Cysteine at position 518 were required for Trabid activity. Flies deficient for Trabid had a reduced life span due to chronic activation of IMD both systemically as well as in their gut where homeostasis was disrupted. The TAK1-associated Binding Protein 2 (TAB2) was linked with the TAK1-Trabid interaction through its Zinc finger domain that pacified the TAK1 signal. These results indicate an elaborate and multi-tiered mechanism for regulating TAK1 activity and modulating its immune signal. Public Library of Science 2014-02-20 /pmc/articles/PMC3930493/ /pubmed/24586180 http://dx.doi.org/10.1371/journal.pgen.1004117 Text en © 2014 Fernando et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Fernando, Merennege Dilan Anush
Kounatidis, Ilias
Ligoxygakis, Petros
Loss of Trabid, a New Negative Regulator of the Drosophila Immune-Deficiency Pathway at the Level of TAK1, Reduces Life Span
title Loss of Trabid, a New Negative Regulator of the Drosophila Immune-Deficiency Pathway at the Level of TAK1, Reduces Life Span
title_full Loss of Trabid, a New Negative Regulator of the Drosophila Immune-Deficiency Pathway at the Level of TAK1, Reduces Life Span
title_fullStr Loss of Trabid, a New Negative Regulator of the Drosophila Immune-Deficiency Pathway at the Level of TAK1, Reduces Life Span
title_full_unstemmed Loss of Trabid, a New Negative Regulator of the Drosophila Immune-Deficiency Pathway at the Level of TAK1, Reduces Life Span
title_short Loss of Trabid, a New Negative Regulator of the Drosophila Immune-Deficiency Pathway at the Level of TAK1, Reduces Life Span
title_sort loss of trabid, a new negative regulator of the drosophila immune-deficiency pathway at the level of tak1, reduces life span
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930493/
https://www.ncbi.nlm.nih.gov/pubmed/24586180
http://dx.doi.org/10.1371/journal.pgen.1004117
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