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APPL1 regulates basal NF-κB activity by stabilizing NIK

APPL1 is a multifunctional adaptor protein that binds membrane receptors, signaling proteins and nuclear factors, thereby acting in endosomal trafficking and in different signaling pathways. Here, we uncover a novel role of APPL1 as a positive regulator of transcriptional activity of NF-κB under bas...

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Autores principales: Hupalowska, Anna, Pyrzynska, Beata, Miaczynska, Marta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482318/
https://www.ncbi.nlm.nih.gov/pubmed/22685329
http://dx.doi.org/10.1242/jcs.105171
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author Hupalowska, Anna
Pyrzynska, Beata
Miaczynska, Marta
author_facet Hupalowska, Anna
Pyrzynska, Beata
Miaczynska, Marta
author_sort Hupalowska, Anna
collection PubMed
description APPL1 is a multifunctional adaptor protein that binds membrane receptors, signaling proteins and nuclear factors, thereby acting in endosomal trafficking and in different signaling pathways. Here, we uncover a novel role of APPL1 as a positive regulator of transcriptional activity of NF-κB under basal but not TNFα-stimulated conditions. APPL1 was found to directly interact with TRAF2, an adaptor protein known to activate canonical NF-κB signaling. APPL1 synergized with TRAF2 to induce NF-κB activation, and both proteins were necessary for this process and function upstream of the IKK complex. Although TRAF2 was not detectable on APPL endosomes, endosomal recruitment of APPL1 was required for its function in the NF-κB pathway. Importantly, in the canonical pathway, APPL1 appeared to regulate the proper spatial distribution of the p65 subunit of NF-κB in the absence of cytokine stimulation, since its overexpression enhanced and its depletion reduced the nuclear accumulation of p65. By analyzing the patterns of gene transcription upon APPL1 overproduction or depletion we found altered expression of NF-κB target genes that encode cytokines. At the molecular level, overexpressed APPL1 markedly increased the level of NIK, the key component of the noncanonical NF-κB pathway, by reducing its association with the degradative complex containing TRAF2, TRAF3 and cIAP1. In turn, high levels of NIK triggered nuclear translocation of p65. Collectively, we propose that APPL1 regulates basal NF-κB activity by modulating the stability of NIK, which affects the activation of p65. This places APPL1 as a novel link between the canonical and noncanonical machineries of NF-κB activation.
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spelling pubmed-34823182012-11-15 APPL1 regulates basal NF-κB activity by stabilizing NIK Hupalowska, Anna Pyrzynska, Beata Miaczynska, Marta J Cell Sci Research Article APPL1 is a multifunctional adaptor protein that binds membrane receptors, signaling proteins and nuclear factors, thereby acting in endosomal trafficking and in different signaling pathways. Here, we uncover a novel role of APPL1 as a positive regulator of transcriptional activity of NF-κB under basal but not TNFα-stimulated conditions. APPL1 was found to directly interact with TRAF2, an adaptor protein known to activate canonical NF-κB signaling. APPL1 synergized with TRAF2 to induce NF-κB activation, and both proteins were necessary for this process and function upstream of the IKK complex. Although TRAF2 was not detectable on APPL endosomes, endosomal recruitment of APPL1 was required for its function in the NF-κB pathway. Importantly, in the canonical pathway, APPL1 appeared to regulate the proper spatial distribution of the p65 subunit of NF-κB in the absence of cytokine stimulation, since its overexpression enhanced and its depletion reduced the nuclear accumulation of p65. By analyzing the patterns of gene transcription upon APPL1 overproduction or depletion we found altered expression of NF-κB target genes that encode cytokines. At the molecular level, overexpressed APPL1 markedly increased the level of NIK, the key component of the noncanonical NF-κB pathway, by reducing its association with the degradative complex containing TRAF2, TRAF3 and cIAP1. In turn, high levels of NIK triggered nuclear translocation of p65. Collectively, we propose that APPL1 regulates basal NF-κB activity by modulating the stability of NIK, which affects the activation of p65. This places APPL1 as a novel link between the canonical and noncanonical machineries of NF-κB activation. The Company of Biologists 2012-09-01 /pmc/articles/PMC3482318/ /pubmed/22685329 http://dx.doi.org/10.1242/jcs.105171 Text en © 2012. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0/), which permits unrestricted non-commercial use, distribution and reproduction in any medium providedthat the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.
spellingShingle Research Article
Hupalowska, Anna
Pyrzynska, Beata
Miaczynska, Marta
APPL1 regulates basal NF-κB activity by stabilizing NIK
title APPL1 regulates basal NF-κB activity by stabilizing NIK
title_full APPL1 regulates basal NF-κB activity by stabilizing NIK
title_fullStr APPL1 regulates basal NF-κB activity by stabilizing NIK
title_full_unstemmed APPL1 regulates basal NF-κB activity by stabilizing NIK
title_short APPL1 regulates basal NF-κB activity by stabilizing NIK
title_sort appl1 regulates basal nf-κb activity by stabilizing nik
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482318/
https://www.ncbi.nlm.nih.gov/pubmed/22685329
http://dx.doi.org/10.1242/jcs.105171
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