Syntaxin-2 inhibits excessive phagocytic uptake but promotes phagolysosomal clearance in macrophages

Abstract

AbstractPhagocytosis maintains host defense and organismal homeostasis by engulfing and eliminating unwanted particles, but defective or uncontrolled phagocytosis can be detrimental. We report here, syntaxin-2 (Stx2), a poorly characterized SNARE in phagocytes, differentially regulates phagocytic uptake and clearance in macrophages. Stx2 is expressed on the inner and outer surfaces of the plasmalemma, early endosomes, VAMP4-positive compartments, and phagosomes. Stx2 knockdown (Stx2-KD) increases entrapment and uptake of IgG-opsonized particles by enhancing formation and expansion of phagocytic cups, driven by elevated trafficking of early endosomes and VAMP4-positive post-Golgi compartments. Additionally, Stx2-KD augments surface expression of Fc receptors, TFEB nuclear translocation, and biogenesis of functional lysosomes. Interestingly, Stx2-KD impedes phagosome acquisition of late endosomes, lysosomes, and vacuolar ATPase, depleting phagosomal cathepsin contents and acidification. Consequently, Stx2-KD macrophages exhibit aberrant uptake of IgG-opsonized bacteria and impaired digestion resulting in increased bacterial load. Thus, Stx2 balances trafficking of non-lytic and lytic compartments to limit excessive uptake while facilitating clearance of the phagocytic particles in macrophages.