Optineurin links Hace1-dependent Rac ubiquitylation to integrin-mediated mechanotransduction to control bacterial invasion and cell division

Serena Petracchini, Daniel Hamaoui, Anne Doye, Atef Asnacios, Florian Fage, Elisa Vitiello, Martial Balland, Sebastien Janel, Frank Lafont, Mukund Gupta, Benoit Ladoux, Jerôme Gilleron, Teresa M. Maia, Francis Impens, Laurent Gagnoux-Palacios, Mads Daugaard, Poul H. Sorensen, Emmanuel Lemichez () and Amel Mettouchi ()
Additional contact information
Serena Petracchini: Université Paris Cité, CNRS UMR6047, INSERM U1306, Unité des Toxines Bactériennes
Daniel Hamaoui: Université Côte d’Azur, INSERM, C3M, Team Microbial Toxins in Host-Pathogen Interactions
Anne Doye: Université Côte d’Azur, INSERM, C3M, Team Microbial Toxins in Host-Pathogen Interactions
Atef Asnacios: Université Paris Cité, CNRS, Laboratoire Matière et Systèmes Complexes, UMR7057
Florian Fage: Université Paris Cité, CNRS, Laboratoire Matière et Systèmes Complexes, UMR7057
Elisa Vitiello: Université Grenoble Alpes, CNRS, LiPhy
Martial Balland: Université Grenoble Alpes, CNRS, LiPhy
Sebastien Janel: Université de Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR9017, CIIL—Center for Infection and Immunity of Lille
Frank Lafont: Université de Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR9017, CIIL—Center for Infection and Immunity of Lille
Mukund Gupta: Université Paris Cité, CNRS, Institut Jacques Monod
Benoit Ladoux: Université Paris Cité, CNRS, Institut Jacques Monod
Jerôme Gilleron: Université Côte d’Azur, INSERM, C3M, Team Cellular and Molecular Pathophysiology of Obesity and Diabetes
Teresa M. Maia: VIB-UGent Center for Medical Biotechnology, VIB
Francis Impens: VIB-UGent Center for Medical Biotechnology, VIB
Laurent Gagnoux-Palacios: Université Côte d’Azur, CNRS, INSERM, Institut de Biologie Valrose (iBV)
Mads Daugaard: Vancouver Prostate Centre
Poul H. Sorensen: University of British Columbia
Emmanuel Lemichez: Université Paris Cité, CNRS UMR6047, INSERM U1306, Unité des Toxines Bactériennes
Amel Mettouchi: Université Paris Cité, CNRS UMR6047, INSERM U1306, Unité des Toxines Bactériennes

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract Extracellular matrix (ECM) elasticity is perceived by cells via focal adhesion structures, which transduce mechanical cues into chemical signalling to conform cell behavior. Although the contribution of ECM compliance to the control of cell migration or division is extensively studied, little is reported regarding infectious processes. We study this phenomenon with the extraintestinal Escherichia coli pathogen UTI89. We show that UTI89 takes advantage, via its CNF1 toxin, of integrin mechanoactivation to trigger its invasion into cells. We identify the HACE1 E3 ligase-interacting protein Optineurin (OPTN) as a protein regulated by ECM stiffness. Functional analysis establishes a role of OPTN in bacterial invasion and integrin mechanical coupling and for stimulation of HACE1 E3 ligase activity towards the Rac1 GTPase. Consistent with a role of OPTN in cell mechanics, OPTN knockdown cells display defective integrin-mediated traction force buildup, associated with limited cellular invasion by UTI89. Nevertheless, OPTN knockdown cells display strong mechanochemical adhesion signalling, enhanced Rac1 activation and increased cyclin D1 translation, together with enhanced cell proliferation independent of ECM stiffness. Together, our data ascribe a new function to OPTN in mechanobiology.

Date: 2022
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DOI: 10.1038/s41467-022-33803-x

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