| First Author | Gupte R | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 3931 |
| PubMed ID | 34168143 | Mgi Jnum | J:343912 |
| Mgi Id | MGI:6725555 | Doi | 10.1038/s41467-021-24225-2 |
| Citation | Gupte R, et al. (2021) Nuclear ADP-ribosylation drives IFNgamma-dependent STAT1alpha enhancer formation in macrophages. Nat Commun 12(1):3931 |
| abstractText | STAT1alpha is a key transcription factor driving pro-inflammatory responses in macrophages. We found that the interferon gamma (IFNgamma)-regulated transcriptional program in macrophages is controlled by ADP-ribosylation (ADPRylation) of STAT1alpha, 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 IFNgamma-stimulated enhancer formation by regulating the genome-wide binding and IFNgamma-dependent transcriptional activation of STAT1alpha. It does so by ADPRylating STAT1alpha on specific residues in its DNA-binding domain (DBD) and transcription activation (TA) domain. ADPRylation of the DBD controls STAT1alpha binding to its cognate DNA elements, whereas ADPRylation of the TA domain regulates enhancer activation by modulating STAT1alpha phosphorylation and p300 acetyltransferase activity. Loss of ADPRylation at either site leads to diminished IFNgamma-dependent transcription and downstream pro-inflammatory responses. We conclude that PARP-1-mediated ADPRylation of STAT1alpha drives distinct enhancer activation mechanisms and is a critical regulator of inflammatory responses in macrophages. |
