2. Academic Validation
  3. PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation

PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation

  • Nat Commun. 2016 Oct 31;7:12849. doi: 10.1038/ncomms12849.
Hiroshi Iwata 1,  Claudia Goettsch 1,  Amitabh Sharma 2 3,  Piero Ricchiuto 1,  Wilson Wen Bin Goh 1,  Arda Halu 1 2,  Iwao Yamada 1,  Hideo Yoshida 1,  Takuya Hara 1,  Mei Wei 4,  Noriyuki Inoue 1,  Daiju Fukuda 1,  Alexander Mojcher 1,  Peter C Mattson 1,  Albert-László Barabási 2 3,  Mark Boothby 4,  Elena Aikawa 1 5,  Sasha A Singh 1,  Masanori Aikawa 1 2 5
Affiliations

Affiliations

  • 1 Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 2 Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 3 Department of Physics, Center for Complex Network Research, Northeastern University, Boston, Massachusetts 02115, USA.
  • 4 Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
  • 5 Center for Excellence in Vascular Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
PMID: 27796300 DOI: 10.1038/ncomms12849
Abstract

Despite the global impact of macrophage activation in vascular disease, the underlying mechanisms remain obscure. Here we show, with global proteomic analysis of macrophage cell lines treated with either IFNγ or IL-4, that PARP9 and PARP14 regulate macrophage activation. In primary macrophages, PARP9 and PARP14 have opposing roles in macrophage activation. PARP14 silencing induces pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells, whereas it suppresses anti-inflammatory gene expression and STAT6 phosphorylation in M(IL-4) cells. PARP9 silencing suppresses pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells. PARP14 induces ADP-ribosylation of STAT1, which is suppressed by PARP9. Mutations at these ADP-ribosylation sites lead to increased phosphorylation. Network analysis links PARP9-PARP14 with human coronary artery disease. PARP14 deficiency in haematopoietic cells accelerates the development and inflammatory burden of acute and chronic arterial lesions in mice. These findings suggest that PARP9 and PARP14 cross-regulate macrophage activation.

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