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

Hiroshi Iwata (), Claudia Goettsch, Amitabh Sharma, Piero Ricchiuto, Wilson Wen Bin Goh, Arda Halu, Iwao Yamada, Hideo Yoshida, Takuya Hara, Mei Wei, Noriyuki Inoue, Daiju Fukuda, Alexander Mojcher, Peter C. Mattson, Albert-László Barabási, Mark Boothby, Elena Aikawa, Sasha A. Singh and Masanori Aikawa ()
Additional contact information
Hiroshi Iwata: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Claudia Goettsch: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Amitabh Sharma: Brigham and Women's Hospital, Harvard Medical School
Piero Ricchiuto: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Wilson Wen Bin Goh: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Arda Halu: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Iwao Yamada: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Hideo Yoshida: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Takuya Hara: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Mei Wei: Vanderbilt University School of Medicine
Noriyuki Inoue: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Daiju Fukuda: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Alexander Mojcher: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Peter C. Mattson: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Albert-László Barabási: Brigham and Women's Hospital, Harvard Medical School
Mark Boothby: Vanderbilt University School of Medicine
Elena Aikawa: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Sasha A. Singh: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School
Masanori Aikawa: Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women’s Hospital, Harvard Medical School

Nature Communications, 2016, vol. 7, issue 1, 1-19

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12849

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