Neutral Sphingomyelinase 2 controls exosomes secretion via counteracting V-ATPase-mediated endosome acidification

During endosome maturation, neutral sphingomyelinase 2 (nSMase2) is involved in intraluminal vesicles (ILVs) budding into late endosomes or multivesicular bodies (MVBs). Fusion of these with the plasma membrane results in exosomes or small extracellular vesicles (sEV) secretion. Here, we describe nSMase2 activity to control sEV secretion through modulation of V-ATPase activity. Specifically, we show that nSMase2 inhibition induces V-ATPase complex assembly that drives MVB lumen acidification and consequently reduces sEV secretion. Conversely, we further demonstrate that stimulating nSMase2 activity with the inflammatory cytokine TNFα decreases acidification and increases sEV secretion. Thus, we find that nSMase2 activity affects MVB membrane lipid composition to counteract V-ATPase-mediated endosome acidification, thereby shifting MVB fate towards sEV secretion.

During endosome maturation, neutral sphingomyelinase 2 (nSMase2) is involved in intraluminal vesicles (ILVs) budding into late endosomes or multivesicular bodies (MVBs). Fusion of these with the plasma membrane results in exosomes or small extracellular vesicles (sEV) secretion. Here, we describe nSMase2 activity to control sEV secretion through modulation of V-ATPase activity. Specifically, we show that nSMase2 inhibition induces V-ATPase complex assembly that drives MVB lumen acidification and consequently reduces sEV secretion. Conversely, we further demonstrate that stimulating nSMase2 activity with the inflammatory cytokine TNFα decreases acidification and increases sEV secretion. Thus, we find that nSMase2 activity affects MVB membrane lipid composition to counteract V-ATPase-mediated endosome acidification, thereby shifting MVB fate towards sEV secretion.