title: PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation.
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.
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Hiroshi
authors: H
authors: Iwata
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Claudia
authors: C
authors: Goettsch
authors: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Physics, Center for Complex Network Research, Northeastern University, Boston, Massachusetts 02115, USA.
authors: Amitabh
authors: A
authors: Sharma
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Piero
authors: 0000-0002-8525-6624
authors: P
authors: Ricchiuto
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Wilson Wen Bin
authors: WW
authors: Goh
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Arda
authors: A
authors: Halu
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Iwao
authors: I
authors: Yamada
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Hideo
authors: H
authors: Yoshida
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Takuya
authors: T
authors: Hara
authors: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: Mei
authors: M
authors: Wei
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Noriyuki
authors: N
authors: Inoue
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Daiju
authors: D
authors: Fukuda
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Alexander
authors: A
authors: Mojcher
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Peter C
authors: PC
authors: Mattson
authors: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Department of Physics, Center for Complex Network Research, Northeastern University, Boston, Massachusetts 02115, USA.
authors: Albert-László
authors: AL
authors: Barabási
authors: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: Mark
authors: M
authors: Boothby
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Center for Excellence in Vascular Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Elena
authors: E
authors: Aikawa
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Sasha A
authors: SA
authors: Singh
authors: Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Center for Excellence in Vascular Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Masanori
authors: M
authors: Aikawa
mesh_terms: D000074744:ADP-Ribosylation; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis; D002470:Cell Survival; D003324:Coronary Artery Disease / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D012266:Ribose / Q000737:chemistry; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D000074084:THP-1 Cells
chemical_list: C508598:IL4 protein, human; D018950:Lipopolysaccharide Receptors; D009363:Neoplasm Proteins; C418133:PARP9 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015847:Interleukin-4; D012266:Ribose; D007371:Interferon-gamma; C584083:PARP14 protein, human; C522628:Parp14 protein, mouse; D011065:Poly(ADP-ribose) Polymerases