The Protein Tyrosine Phosphatase SHP-1 Regulates Phagolysosome Biogenesis

Abstract

The process of phagocytosis and phagosome maturation involves the recruitment of effector proteins that participate in phagosome formation and in the acidification and/or fusion with various endocytic vesicles. In the current study, we investigated the role of the Src homology region 2 domain-containing phosphatase 1 (SHP-1) in phagolysosome biogenesis. To this end, we used immortalized bone marrow macrophages derived from SHP-1–deficient motheaten mice and their wild-type littermates. We found that SHP-1 is recruited early and remains present on phagosomes for up to 4 h postphagocytosis. Using confocal immunofluorescence microscopy and Western blot analyses on purified phagosome extracts, we observed an impaired recruitment of lysosomal-associated membrane protein 1 in SHP-1–deficient macrophages. Moreover, Western blot analyses revealed that whereas the 51-kDa procathepsin D is recruited to phagosomes, it is not processed into the 46-kDa cathepsin D in the absence of SHP-1, suggesting a defect in acidification. Using the lysosomotropic agent LysoTracker as an indicator of phagosomal pH, we obtained evidence that in the absence of SHP-1, phagosome acidification was impaired. Taken together, these results are consistent with a role for SHP-1 in the regulation of signaling or membrane fusion events involved in phagolysosome biogenesis.

Dengue virus compartmentalization during antibody-enhanced infection

“…SHP-1 is thought to inhibit phagosome acidification by acting on membrane fusion during phagosome trafficking19. Defects in phagosome acidification have also been observed in SHP-1 deficient mouse macrophages27. Our findings thus agree with recent studies that have demonstrated increased viral fusion during ADE, which leads to enhanced production of infectious DENV titres28.…”

Trehalose dimycolate interferes with FcγR-mediated phagosome maturation through Mincle, SHP-1 and FcγRIIB signalling

“…These authors demonstrated that recognition of the parasites by Mincle triggers an inhibitory FcγR-SHP-1 axis in dendritic cells subsequently leading to down-regulation of Th 1 responses required for protective immunity to Leishmania parasites. Finally, our findings differ from a recent study showing that SHP-1 promotes non-opsonised bead-phagosome maturation [28] indicating that SHP-1 has differential regulatory functions depending on whether phagocytosis is mediated by FcγR or other receptors.…”

p85α recruitment by the CD300f phosphatidylserine receptor mediates apoptotic cell clearance required for autoimmunity suppression

“…Most likely, SHP1 is the phosphatase involved in the inhibitory signalling, as it associates with CD300f in J774 and HeLa cells, and SHP1 overexpression decreases CD300f-mediated AC phagocytosis in a dose-dependent manner. In agreement, SHP1 has been shown to be recruited to Fc receptor-mediated phagosomes and negatively regulate phagocytosis 51,52 . The maximal association between CD300f and SHP1 has been reported to require several tyrosines (Y241, Y289 and Y325) 32 .…”