Mycobacterium tuberculosis Controls Phagosomal Acidification by Targeting CISH-Mediated Signaling

Christophe J. Queval, Ok Ryul Song, Jean Philippe Carralot, Jean Michel Saliou, Antonino Bongiovanni, Gaspard Deloison, Nathalie Deboosère, Samuel Jouny, Raffaella Iantomasi, Vincent Delorme, Anne Sophie Debrie, Sei Jin Park, Joana Costa Gouveia, Stanislas Tomavo, Roland Brosch, Akihiko Yoshimura, Edouard Yeramian, Priscille Brodin

研究成果: Article査読

47 被引用数 (Scopus)


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. Mycobacterium tuberculosis is effective at controlling phagosomal acidification. Queval et al. unravel a cellular mechanism underlying this defense strategy and show that the pathogen interferes with host pathways. The CISH protein triggers ubiquitination and degradation of H+-V-ATPase, thus shutting down the proton pump.

ジャーナルCell Reports
出版ステータスPublished - 2017 9月 26

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)


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