Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils.,Journal of Experimental Medicine

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Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils.
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2019-09-06 , DOI: 10.1084/jem.20180371
Delphine Ohayon _{1,

2} , Alessia De Chiara _{1,

2} , Pham My-Chan Dang _{2,

3} , Nathalie Thieblemont _{1,

2} , Simon Chatfield _{1,

2} , Viviana Marzaioli _{2,

3} , Sabrina Sofia Burgener _{4,

5} , Julie Mocek _{1,

2} , Céline Candalh _{1,

2} , Coralie Pintard _{2,

3} , Pascale Tacnet-Delorme ₆ , Gilles Renault _{1,

2} , Isabelle Lagoutte _{1,

2} , Maryline Favier _{1,

2} , Francine Walker ₇ , Margarita Hurtado-Nedelec _{2,

3} , Dominique Desplancq ₈ , Etienne Weiss ₈ , Charaf Benarafa _{4,

5} , Dominique Housset ₆ , Jean-Claude Marie _{2,

3} , Philippe Frachet ₆ , Jamel El-Benna _{2,

3} , Véronique Witko-Sarsat _{2,

9}

Affiliation

Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France.
LabEx Inflamex, Sorbonne Paris Cité, Paris, France.
Institut National de la Santé et de la Recherche Médicale U1149, Centre National de la Recherche Scientifique ERL8252, Centre de Recherche sur l'Inflammation, Université Paris Diderot, Faculté de Médecine, Site Xavier Bichat, Paris, France.
Institute of Virology and Immunology, Mittelhäusern, Switzerland.
Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Université Grenoble Alpes, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Centre National de la Recherche Scientifique, Institut de Biologie Structurale, Grenoble, France.
Department of Pathology, Bichat Hospital, Paris, France.
Ecole Supérieure de Biotechnologie de Strasbourg, Centre National de la Recherche Scientifique UMR 7242, Université de Strasbourg, Strasbourg, France.
Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France

Neutrophils produce high levels of reactive oxygen species (ROS) by NADPH oxidase that are crucial for host defense but can lead to tissue injury when produced in excess. We previously described that proliferating cell nuclear antigen (PCNA), a nuclear scaffolding protein pivotal in DNA synthesis, controls neutrophil survival through its cytosolic association with procaspases. We herein showed that PCNA associated with p47phox, a key subunit of NADPH oxidase, and that this association regulated ROS production. Surface plasmon resonance and crystallography techniques demonstrated that the interdomain-connecting loop of PCNA interacted directly with the phox homology (PX) domain of the p47phox. PCNA inhibition by competing peptides or by T2AA, a small-molecule PCNA inhibitor, decreased NADPH oxidase activation in vitro. Furthermore, T2AA provided a therapeutic benefit in mice during trinitro-benzene-sulfonic acid (TNBS)-induced colitis by decreasing oxidative stress, accelerating mucosal repair, and promoting the resolution of inflammation. Our data suggest that targeting PCNA in inflammatory neutrophils holds promise as a multifaceted antiinflammatory strategy.

中文翻译：

胞质PCNA与p47phox相互作用并控制嗜中性粒细胞中NADPH氧化酶NOX2的活化。

中性粒细胞通过NADPH氧化酶产生高水平的活性氧（ROS），这对于宿主防御至关重要，但过量产生时会导致组织损伤。我们以前曾描述过增殖的细胞核抗原（PCNA），一种在DNA合成中起关键作用的核支架蛋白，通过其与procaspase的胞质结合来控制嗜中性粒细胞的存活。我们在本文中显示PCNA与p47phox（NADPH氧化酶的关键亚基）相关，并且该关联调节ROS的产生。表面等离子体共振和晶体学技术表明，PCNA的域间连接环直接与p47phox的phox同源性（PX）域相互作用。竞争性肽或小分子PCNA抑制剂T2AA对PCNA的抑制作用可降低NADPH氧化酶的体外活化。此外，在三硝基苯磺酸（TNBS）诱导的结肠炎中，T2AA通过降低氧化应激，加速粘膜修复并促进炎症消退，为小鼠提供了治疗益处。我们的数据表明，靶向PCNA在炎症性中性粒细胞中有望作为多方面的抗炎策略。

更新日期：2019-11-04

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