STIM1 Juxtaposes ER to Phagosomes, Generating Ca²⁺ Hotspots That Boost Phagocytosis

Curr Biol. 2012 Nov 6;22(21):1990-7. doi: 10.1016/j.cub.2012.08.049. Epub 2012 Oct 4.

Abstract

Background: Endoplasmic reticulum (ER) membranes are recruited to phagosomes, but the mechanism and functional significance of this ER recruitment is not known. Here, we show that the ER Ca(2+) sensor stromal interaction molecule 1 (STIM1) sustains high-efficiency phagocytosis by recruiting thin ER cisternae that interact productively but do not fuse with phagosomes.

Results: Endogenous STIM1 was recruited to phagosomes upon ER Ca(2+) depletion in mouse neutrophils, and exogenous YFP-STIM1 puncta coincided with localized Ca(2+) elevations around phagosomes in fibroblasts expressing phagocytic receptors. STIM1 ablation decreased phagocytosis, ER-phagosome contacts, and periphagosomal Ca(2+) elevations in both neutrophils and fibroblasts, whereas STIM1 re-expression in Stim1(-/-) fibroblasts rescued these defects, promoted the formation and elongation of tight ER-phagosome contacts upon ER Ca(2+) depletion and increased the shedding of periphagosomal actin rings. Re-expression of a signaling-deficient STIM1 mutant unable to open Ca(2+) channels recruited ER cisternae to the vicinity of phagosomes but failed to rescue phagocytosis, actin shedding, and periphagosomal Ca(2+) elevations. The periphagosomal Ca(2+) hotspots were decreased by extracellular Ca(2+) chelation and by Ca(2+) channels inhibitors, revealing that the Ca(2+) ions originate at least in part from phagosomes.

Conclusions: Our findings indicate that STIM1 recruits ER cisternae near phagosomes for signaling purposes and that the opening of phagosomal Ca(2+) channels generates localized Ca(2+) elevations that promote high-efficiency phagocytosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / analysis*
  • Calcium Channel Blockers
  • Calcium Channels / metabolism
  • Calcium Signaling
  • Cell Line
  • Endoplasmic Reticulum / metabolism*
  • HL-60 Cells
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / metabolism
  • Phagocytosis*
  • Phagosomes / metabolism*
  • Signal Transduction
  • Stromal Interaction Molecule 1
  • Tight Junctions

Substances

  • Calcium Channel Blockers
  • Calcium Channels
  • Membrane Glycoproteins
  • Stim1 protein, mouse
  • Stromal Interaction Molecule 1
  • Calcium