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Soluble adenylyl cyclase is essential for proper lysosomal acidification.

TitleSoluble adenylyl cyclase is essential for proper lysosomal acidification.
Publication TypeJournal Article
Year of Publication2016
AuthorsRahman N, Ramos-Espiritu L, Milner TA, Buck J, Levin LR
JournalJ Gen Physiol
Volume148
Issue4
Pagination325-39
Date Published2016 Oct
ISSN1540-7748
KeywordsAdenylyl Cyclases, Animals, Brain, Cell Line, Fibroblasts, Gene Expression Regulation, Enzymologic, Lysosomes, Mice, Mice, Knockout, Purines
Abstract

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.

DOI10.1085/jgp.201611606
Alternate JournalJ. Gen. Physiol.
PubMed ID27670898
PubMed Central IDPMC5037342
Grant ListF31 NS081930 / NS / NINDS NIH HHS / United States
R01 GM062328 / GM / NIGMS NIH HHS / United States
R01 GM107442 / GM / NIGMS NIH HHS / United States
R01 NS055255 / NS / NINDS NIH HHS / United States