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

Research output: Contribution to journalArticlepeer-review

47 Citations (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.

Original languageEnglish
Pages (from-to)3188-3198
Number of pages11
JournalCell Reports
Issue number13
Publication statusPublished - 2017 Sept 26


  • CISH
  • GM-CSF
  • H V-ATPase
  • Mycobacterium tuberculosis
  • STAT5
  • high-content imaging
  • macrophages
  • phagosome acidification
  • protosomal degradation
  • ubiquitination

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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