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Correction: CD38 produces nicotinic acid adenine dinucleotide phosphate in the lysosome
- Source :
- Journal of Biological Chemistry. 294:19447
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Nicotinic acid adenosine dinucleotide phosphate (NAADP) is a Ca(2+)-mobilizing second messenger that regulates a wide range of biological activities. However, the mechanism of its biogenesis remains controversial. CD38 is the only enzyme known to catalyze NAADP synthesis from NADP and nicotinic acid. CD38-mediated catalysis requires an acidic pH, suggesting that NAADP may be produced in acidic endolysosomes, but this hypothesis is untested. In this study, using human cell lines, we specifically directed CD38 to the endolysosomal system and assessed cellular NAADP production. First, we found that nanobodies targeting various epitopes on the C-terminal domain of CD38 could bind to cell surface–localized CD38 and induce its endocytosis. We also found that CD38 internalization occurred via a clathrin-dependent pathway, delivered CD38 to the endolysosome, and elevated intracellular NAADP levels. We also created a CD38 variant for lysosome-specific expression, which not only withstood the degradative environment in the lysosome, but was also much more active than WT CD38 in elevating cellular NAADP levels. Supplementing CD38-expressing cells with nicotinic acid substantially increased cellular NAADP levels. These results demonstrate that endolysosomal CD38 can produce NAADP in human cells. They further suggest that CD38's compartmentalization to the lysosome may allow for its regulation via substrate access, rather than enzyme activation, thereby providing a reliable mechanism for regulating cellular NAADP production.
- Subjects :
- Vasodilator Agents
CD38
Niacin
Biochemistry
chemistry.chemical_compound
immune system diseases
hemic and lymphatic diseases
Lysosome
medicine
Humans
Calcium Signaling
Molecular Biology
Membrane Glycoproteins
Nicotinic acid adenine dinucleotide phosphate
hemic and immune systems
Cell Biology
Single-Domain Antibodies
ADP-ribosyl Cyclase 1
Endocytosis
HEK293 Cells
medicine.anatomical_structure
chemistry
Additions and Corrections
Calcium
Lysosomes
NADP
HeLa Cells
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 294
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....2af8c5d06f61e48f31fbdc597c845f8a