Soluble adenylyl cyclase is essential for proper lysosomal acidification.
Lysosomes, the degradative organelles of the endocytic and autophagic pathways, function at an acidic pH. Lysosomes are acidified by the proton-pumping vacuolar ATPase (V-ATPase), but the molecular processes that set the organelle's pH are not completely understood. In particular, pH-sensitive signaling enzymes that can regulate lysosomal acidification in steady-state physiological conditions have yet to be identified. Soluble adenylyl cyclase (sAC) is a widely expressed source of cAMP that serves as a physiological pH sensor in cells. For example, in proton-secreting epithelial cells, sAC is responsible for pH-dependent translocation of V-ATPase to the luminal surface. Here we show genetically and pharmacologically that sAC is also essential for lysosomal acidification. In the absence of sAC, V-ATPase does not properly localize to lysosomes, lysosomes fail to fully acidify, lysosomal degradative capacity is diminished, and autophagolysosomes accumulate.
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065 Graduate Program in Neuroscience, Weill Cornell Medical College, New York, NY 10065.
Nawreen
N
Rahman
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065.
Lavoisier
L
Ramos-Espiritu
Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065 Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065.
Teresa A
TA
Milner
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065 jobuck@med.cornell.edu.
Jochen
J
Buck
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065.
Lonny R
LR
Levin
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D008247:Lysosomes; D051379:Mice; D018345:Mice, Knockout; D011687:Purines
C569692:PH006 compound; D011687:Purines; D000262:Adenylyl Cyclases
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