Mycobacterium tuberculosis Controls Phagosomal Acidification by Targeting CISH-Mediated Signaling

Christophe J Queval (1, 2) , Ok-Ryul Song (3, 1) , Jean-Philippe Carralot (3) , Jean-Michel Saliou (1, 4) , Antonino Bongiovanni (1) , Gaspard Deloison (1) , Nathalie Deboosere (1) , Samuel J Jouny (1) , Raffaella Iantomasi (1) , Vincent Delorme (1, 3) , Anne-Sophie Debrie (1) , Sei-Jin Park (3) , Joana Costa Gouveia (1) , Stanislas Tomavo (1) , Roland Brosch (2) , Akihiko Yoshimura (5) , Edouard Yeramian (6) , Priscille Brodin (1, 3)

1 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
2 Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics
3 Institut Pasteur Korea - Institut Pasteur de Corée
4 P3M - Protéomique et Peptides Modifiés - PLBS
5 Keio University School of Medicine [Tokyo, Japan]
6 Microb. Struc. (UMR_3528 / U-Pasteur_5) - Microbiologie structurale - Structural Microbiology

Pathogens have evolved a range of mechanisms to counteract host defenses, notably to survive harsh acidic conditions in phagosomes. In the case of Mycobacterium tuberculosis, it has been shown that regulation of phagosome acidification could be achieved by interfering with the retention of the V-ATPase complexes at the vacuole. Here, we present evidence that M. tuberculosis resorts to yet another strategy to control phagosomal acidification, interfering with host suppressor of cytokine signaling (SOCS) protein functions. More precisely, we show that infection of macrophages with M. tuberculosis leads to granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion, inducing STAT5-mediated expression of cytokine-inducible SH2-containing protein (CISH), which selectively targets the V-ATPase catalytic subunit A for ubiquitination and degradation by the proteasome. Consistently, we show that inhibition of CISH expression leads to reduced replication of M. tuberculosis in macrophages. Our findings further broaden the molecular understanding of mechanisms deployed by bacteria to survive.

Mots clés: CISH; GM-CSF; H(+) V-ATPase; Mycobacterium tuberculosis; STAT5; high-content imaging; macrophages; phagosome acidification; protosomal degradation; ubiquitination

Domaines: Maladies infectieuses; Interactions cellulaires [q-bio.CB]; Génétique humaine; Pneumologie et système respiratoire; Bactériologie

Christophe J Queval, Ok-Ryul Song, Jean-Philippe Carralot, Jean-Michel Saliou, Antonino Bongiovanni, et al.. Mycobacterium tuberculosis Controls Phagosomal Acidification by Targeting CISH-Mediated Signaling. Cell Reports, 2017, 20 (13), pp.3188-3198. ⟨10.1016/j.celrep.2017.08.101⟩. ⟨pasteur-02046436⟩