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Human DUX4 and mouse Dux interact with STAT1 and broadly inhibit interferon-stimulated gene induction
Amy E Spens1, Nicholas A Sutliff1, Sean R Bennett1
1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
Abstract:
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.
Insights
DUX4 protein suppresses immune signaling by interacting with STAT1, inhibiting interferon-stimulated genes. This mechanism is relevant to facioscapulohumeral dystrophy (FSHD) and cancer immune evasion.
Area of Science:
- Molecular Biology
- Immunology
- Developmental Biology
Background:
- DUX4 protein is crucial for early embryonic gene expression.
- DUX4 mis-expression is linked to facioscapulohumeral dystrophy (FSHD) and cancer immune evasion.
- DUX4 suppresses major histocompatibility complex class I (MHC class I) expression, aiding cancer immune evasion.
Purpose of the Study:
- To investigate the molecular mechanism by which DUX4 suppresses immune signaling.
- To determine DUX4's interaction with STAT1 and its effect on interferon-stimulated genes (ISGs).
- To explore the implications of DUX4's immune-modulating role in FSHD and cancer.
Main Methods:
- Protein-protein interaction studies between DUX4 and STAT1.
- Analysis of STAT1 and Pol-II recruitment to ISG promoters.
- Functional assays in FSHD and cancer cell lines expressing DUX4.
- Comparative studies using mouse Dux.
Main Results:
- DUX4 interacts with STAT1, broadly suppressing IFNγ-stimulated genes.
- Suppression of ISGs requires specific motifs in DUX4 and is enhanced by STAT1 phosphorylation.
- Endogenous DUX4 in FSHD cells and DUX4 fusions in cancer cells inhibit IFNγ induction of ISGs.
- Mouse Dux exhibits similar interactions and suppression of ISGs.
Conclusions:
- DUX4 modulates immune signaling pathways by interacting with STAT1.
- This interaction leads to the suppression of interferon-stimulated genes, impacting immune evasion in cancers.
- The findings highlight an evolved role for DUXC family proteins in development, cancer, and FSHD.
