Nuclear ADP-ribosylation drives IFNγ-dependent STAT1α enhancer formation in macrophages

STAT1 alpha is a key transcription factor driving pro-inflammatory responses in macrophages. We found that the interferon gamma (IFN gamma)-regulated transcriptional program in macrophages is controlled by ADP-ribosylation (ADPRylation) of STAT1 alpha, a post-translational modification resulting in the site-specific covalent attachment of ADP-ribose moieties. PARP-1, the major nuclear poly(ADP-ribose) polymerase (PARP), supports IFN gamma -stimulated enhancer formation by regulating the genome-wide binding and IFN gamma -dependent transcriptional activation of STAT1 alpha. It does so by ADPRylating STAT1 alpha on specific residues in its DNA-binding domain (DBD) and transcription activation (TA) domain. ADPRylation of the DBD controls STAT1 alpha binding to its cognate DNA elements, whereas ADPRylation of the TA domain regulates enhancer activation by modulating STAT1 alpha phosphorylation and p300 acetyltransferase activity. Loss of ADPRylation at either site leads to diminished IFN gamma -dependent transcription and downstream pro-inflammatory responses. We conclude that PARP-1-mediated ADPRylation of STAT1 alpha drives distinct enhancer activation mechanisms and is a critical regulator of inflammatory responses in macrophages. STAT1a is required for pro-inflammatory responses in macrophages. Here the authors reveal that post-translational modification of STAT1a, ADPribosylation, plays a critical role in enhancer formation and activation, thus modulating IFN gamma -stimulated inflammatory responses in macrophages.

Automated summary

The study demonstrates that ADP-ribosylation of STAT1a by PARP-1 plays a crucial role in controlling enhancer formation and activation, thereby modulating IFN gamma-stimulated inflammatory responses in macrophages.