Pneumococcus triggers NFkB degradation in COMMD2 aggresome-like bodies

Michael G Connor (1) , Lisa Sanchez (2) , Christine Chevalier (1) , Filipe Carvalho (3) , Matthew G Eldridge (1) , Thibault Chaze (4) , Mariette Matondo (4) , Caroline M Weight (5) , Robert S Heyderman (5) , Jost Enninga (2) , Melanie A Hamon (1)

1 Chromatine et Infection - Chromatin and Infection
2 Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions
3 MICALIS - MICrobiologie de l'ALImentation au Service de la Santé
4 UTechS MSBio - Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology
5 UCL - University College of London [London]

NF-kB driven cellular immunity is essential for both pro- and anti-inflammatory responses to microbes, which makes it one of the most frequently targeted pathways by bacteria during pathogenesis. How NF-kB tunes the epithelial response to Streptococcus pneumoniae across the spectrum of commensal to pathogenic host phenotypic outcomes is not fully understood. In this study, we compare a commensal-like 6B ST90 strain to an invasive TIGR4 isolate and demonstrate that TIGR4 both blunts and antagonizes NF-kB activation. We identified, through comparative mass spectrometry of the p65 interactome, that the 6B ST90 isolate drives a non-canonical NF-kB RelB cascade, whereas TIGR4 induces p65 degradation though aggrephagy. Mechanistically, we show that during TIGR4 challenge a novel interaction of COMMD2 with p65 and p62 is established to mediate degradation of p65. With these results, we establish a role for COMMD2 in negative NF-kB regulation, and present a paradigm for diverging NF-kB responses to pneumococcus. Thus, our studies reveal for the first time a new bacterial pathogenesis mechanism to repress host inflammatory response though COMMD2 mediated turnover of p65.

Domaines: Sciences du Vivant [q-bio]

Michael G Connor, Lisa Sanchez, Christine Chevalier, Filipe Carvalho, Matthew G Eldridge, et al.. Pneumococcus triggers NFkB degradation in COMMD2 aggresome-like bodies. 2023. ⟨pasteur-04097504⟩