Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils.

Ohayon, Delphine; De Chiara, Alessia; Dang, Pham My-Chan; Thieblemont, Nathalie; Chatfield, Simon; Marzaioli, Viviana; Burgener, Sabrina Sofia; Mocek, Julie; Candalh, Céline; Pintard, Coralie; Tacnet-Delorme, Pascale; Renault, Gilles; Lagoutte, Isabelle; Favier, Maryline; Walker, Francine; Hurtado-Nedelec, Margarita; Desplancq, Dominique; Weiss, Etienne; Benarafa, Charaf; Housset, Dominique; ... (2019). Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils. Journal of experimental medicine, 216(11), pp. 2669-2687. Rockefeller University Press 10.1084/jem.20180371

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Virology and Immunology

UniBE Contributor:

Benarafa, Charaf

Subjects:

600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1540-9538

Publisher:

Rockefeller University Press

Language:

English

Submitter:

Achim Braun Parham

Date Deposited:

26 Feb 2020 08:12

Last Modified:

07 Mar 2020 02:30

Publisher DOI:

10.1084/jem.20180371

PubMed ID:

31492810

BORIS DOI:

10.7892/boris.140301

URI:

https://boris.unibe.ch/id/eprint/140301

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