Abstract
SummaryPathogens 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.
Highlights
Biological acids play key roles in the innate immune responses of eukaryotic hosts
We further show that entry of Mycobacterium tuberculosis (Mtb) in macrophages induces rapid release of granulocytemacrophage colony-stimulating factors (GM-CSFs), triggering STAT5 signaling and leading to early CISH expression
CISH Promotes Mtb Replication To study the effect of Cish on intracellular replication of Mtb, we used the visual phenotypic assay in murine macrophages
Summary
Biological acids play key roles in the innate immune responses of eukaryotic hosts. To counteract acid-mediated defense mechanisms, encountered at extracellular or intracellular levels, pathogens have evolved a range of strategies. It was previously suggested that, in this case, such stabilization is caused by a defective retention of the V-ATPase complex at the phagosome (Pethe et al, 2004; Sturgill-Koszycki et al, 1994) Accounting for this phenomenon, it was shown that the microbial tyrosine phosphatase PtpA (Rv2234) prevents the tethering of V-ATPase to the Mtb-containing vacuole (Wong et al, 2011). Whereas it is considered that the Mtb phagosome remains immature (Armstrong and Hart, 1971; Russell, 2001), studies showed that Mtb is able to induce phagosomal rupture at later stages of infection (Simeone et al, 2012; van der Wel et al, 2007) This capacity depends on a functional ESX-1 type VII secretion system and requires control of phagosomal acidification (Simeone et al, 2015). These observations hint to the possible existence of alternative mechanisms, which could be used by pathogenic mycobacteria to block phagosomal acidification
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