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mBio. 2019 Dec 17;10(6). pii: e02778-19. doi: 10.1128/mBio.02778-19.

Ubiquitination of Listeria Virulence Factor InlC Contributes to the Host Response to Infection.

Gouin E1,2,3, Balestrino D1,2,3, Rasid O4, Nahori MA1,2,3, Villiers V1,2,3, Impens F1,2,3, Volant S5,6, Vogl T7, Jacob Y8,9,10, Dussurget O11,2,3,10, Cossart P11,2,3.

Author information

1
Institut Pasteur, Unité des Interactions Bactéries-Cellules, Paris, France.
2
Inserm, U604, Paris, France.
3
INRA, USC2020, Paris, France.
4
Institut Pasteur, Groupe à 5 ans Chromatine et Infection, Paris, France.
5
Institut Pasteur, Hub Bioinformatique et Biostatistique, Paris, France.
6
CNRS, USR3756, Paris, France.
7
Institute of Immunology, University of Münster, Münster, Germany.
8
Institut Pasteur, Unité de Génétique Moléculaire des Virus à ARN, Paris, France.
9
CNRS, UMR3569, Paris, France.
10
Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
11
Institut Pasteur, Unité des Interactions Bactéries-Cellules, Paris, France olivier.dussurget@pasteur.fr pascale.cossart@pasteur.fr.

Abstract

Listeria monocytogenes is a pathogenic bacterium causing potentially fatal foodborne infections in humans and animals. While the mechanisms used by Listeria to manipulate its host have been thoroughly characterized, how the host controls bacterial virulence factors remains to be extensively deciphered. Here, we found that the secreted Listeria virulence protein InlC is monoubiquitinated by the host cell machinery on K224, restricting infection. We show that the ubiquitinated form of InlC interacts with the intracellular alarmin S100A9, resulting in its stabilization and in increased reactive oxygen species production by neutrophils in infected mice. Collectively, our results suggest that posttranslational modification of InlC exacerbates the host response upon Listeria infection.IMPORTANCE The pathogenic potential of Listeria monocytogenes relies on the production of an arsenal of virulence determinants that have been extensively characterized, including surface and secreted proteins of the internalin family. We have previously shown that the Listeria secreted internalin InlC interacts with IκB kinase α to interfere with the host immune response (E. Gouin, M. Adib-Conquy, D. Balestrino, M.-A. Nahori, et al., Proc Natl Acad Sci USA, 107:17333-17338, 2010, https://doi.org/10.1073/pnas.1007765107). In the present work, we report that InlC is monoubiquitinated on K224 upon infection of cells and provide evidence that ubiquitinated InlC interacts with and stabilizes the alarmin S100A9, which is a critical regulator of the immune response and inflammatory processes. Additionally, we show that ubiquitination of InlC causes an increase in reactive oxygen species production by neutrophils in mice and restricts Listeria infection. These findings are the first to identify a posttranscriptional modification of an internalin contributing to host defense.

KEYWORDS:

Listeria monocytogenes ; alarmin; inflammation; pathogenesis; ubiquitination

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