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| Status |
Public on Nov 01, 2022 |
| Title |
Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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 IFNg-induction of MHC Class I and contributes to immune evasion. We show that the DUX4 protein broadly suppresses immune signaling pathways—including IFNg, IFNb, DDX58, IFIH1 and cGAS mediated pathways. A conserved region containing (L)LxxL(L) motifs in the DUX4 carboxyterminal domain (CTD) was necessary to suppress interferon stimulated genes (ISGs). Co-immunoprecipitation identified DUX4-CTD interaction with multiple immune signaling factors, including STAT1. The DUX4-CTD (L)LxxL(L) region interacts with phosphorylated STAT1, sequesters it in the nucleus, modestly reduces its DNA binding, and prevents STAT1 from inducing ISG transcription. Mouse Dux similarly interacted with STAT1 and suppressed IFNg 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.
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| |
|
| Overall design |
Examination of mRNA expression in two DUX4 mutants, F67A and aa154-424
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| |
|
| Contributor(s) |
Spens A, Bennett S, Tapscott SJ |
| Citation(s) |
37092726 |
| |
| Submission date |
Oct 20, 2021 |
| Last update date |
May 10, 2023 |
| Contact name |
Stephen Tapscott |
| E-mail(s) |
stapscot@fredhutch.org
|
| Organization name |
Fred Hutchinson Cancer Research Center
|
| Street address |
1100 Fairview Ave N, Room C3-123
|
| City |
Seattle |
| State/province |
Washington |
| ZIP/Postal code |
98109 |
| Country |
USA |
| |
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| Platforms (1) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA773067 |
| SRA |
SRP342322 |
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