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Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction
DUX4 activates the first wave of zygotic gene expression in the early embryo. Mis-expression of DUX4 in skeletal muscle causes facioscapulohumeral dystrophy (FSHD), whereas expression in cancers suppresses IFNγ induction of major histocompatibility complex class I (MHC class I) and contributes to im...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10195082/ https://www.ncbi.nlm.nih.gov/pubmed/37092726 http://dx.doi.org/10.7554/eLife.82057 |
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author | Spens, Amy E Sutliff, Nicholas A Bennett, Sean R Campbell, Amy E Tapscott, Stephen J |
author_facet | Spens, Amy E Sutliff, Nicholas A Bennett, Sean R Campbell, Amy E Tapscott, Stephen J |
author_sort | Spens, Amy E |
collection | PubMed |
description | DUX4 activates the first wave of zygotic gene expression in the early embryo. Mis-expression of DUX4 in skeletal muscle causes facioscapulohumeral dystrophy (FSHD), whereas expression in cancers suppresses IFNγ induction of major histocompatibility complex class I (MHC class I) and contributes to immune evasion. We show that the DUX4 protein interacts with STAT1 and broadly suppresses expression of IFNγ-stimulated genes by decreasing bound STAT1 and Pol-II recruitment. Transcriptional suppression of interferon-stimulated genes (ISGs) requires conserved (L)LxxL(L) motifs in the carboxyterminal region of DUX4 and phosphorylation of STAT1 Y701 enhances interaction with DUX4. Consistent with these findings, expression of endogenous DUX4 in FSHD muscle cells and the CIC-DUX4 fusion containing the DUX4 CTD in a sarcoma cell line inhibit IFNγ induction of ISGs. Mouse Dux similarly interacted with STAT1 and suppressed IFNγ induction of ISGs. These findings identify an evolved role of the DUXC family in modulating immune signaling pathways with implications for development, cancers, and FSHD. |
format | Online Article Text |
id | pubmed-10195082 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-101950822023-05-19 Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction Spens, Amy E Sutliff, Nicholas A Bennett, Sean R Campbell, Amy E Tapscott, Stephen J eLife Developmental Biology DUX4 activates the first wave of zygotic gene expression in the early embryo. Mis-expression of DUX4 in skeletal muscle causes facioscapulohumeral dystrophy (FSHD), whereas expression in cancers suppresses IFNγ induction of major histocompatibility complex class I (MHC class I) and contributes to immune evasion. We show that the DUX4 protein interacts with STAT1 and broadly suppresses expression of IFNγ-stimulated genes by decreasing bound STAT1 and Pol-II recruitment. Transcriptional suppression of interferon-stimulated genes (ISGs) requires conserved (L)LxxL(L) motifs in the carboxyterminal region of DUX4 and phosphorylation of STAT1 Y701 enhances interaction with DUX4. Consistent with these findings, expression of endogenous DUX4 in FSHD muscle cells and the CIC-DUX4 fusion containing the DUX4 CTD in a sarcoma cell line inhibit IFNγ induction of ISGs. Mouse Dux similarly interacted with STAT1 and suppressed IFNγ induction of ISGs. These findings identify an evolved role of the DUXC family in modulating immune signaling pathways with implications for development, cancers, and FSHD. eLife Sciences Publications, Ltd 2023-04-24 /pmc/articles/PMC10195082/ /pubmed/37092726 http://dx.doi.org/10.7554/eLife.82057 Text en © 2023, Spens et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Developmental Biology Spens, Amy E Sutliff, Nicholas A Bennett, Sean R Campbell, Amy E Tapscott, Stephen J Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction |
title | Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction |
title_full | Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction |
title_fullStr | Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction |
title_full_unstemmed | Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction |
title_short | Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction |
title_sort | human dux4 and mouse dux interact with stat1 and broadly inhibit interferon-stimulated gene induction |
topic | Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10195082/ https://www.ncbi.nlm.nih.gov/pubmed/37092726 http://dx.doi.org/10.7554/eLife.82057 |
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