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CD38 produces nicotinic acid adenosine dinucleotide phosphate in the lysosome
- Source :
- Journal of Biological Chemistry. 293:8151-8160
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Nicotinic acid adenosine dinucleotide phosphate (NAADP) is a Ca2+-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 :
- 0301 basic medicine
030102 biochemistry & molecular biology
Chemistry
media_common.quotation_subject
hemic and immune systems
Cell Biology
Endocytosis
Biochemistry
Endolysosome
Cell biology
03 medical and health sciences
Enzyme activator
030104 developmental biology
medicine.anatomical_structure
immune system diseases
hemic and lymphatic diseases
Lysosome
Second messenger system
medicine
Internalization
Molecular Biology
Intracellular
media_common
Calcium signaling
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 293
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi...........0a4a9e8d0eef9898f62d058fa9e02103