Journal
FASEB JOURNAL
Volume 34, Issue 9, Pages 12565-12576Publisher
WILEY
DOI: 10.1096/fj.202001249R
Keywords
calcium; cell migration; nicotinamide adenine dinucleotide; signal transduction
Categories
Funding
- National Research Foundation of Korea (NRF) [2012R1A3A2026453, 2014R1A6A1030318]
- Roy J. Carver Trust
- National Research Foundation of Korea [2014R1A6A1030318] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca(2+)mobilizing second messenger whose formation has remained elusive. In vitro, CD38-mediated NAADP synthesis requires an acidic pH and a nonphysiological concentration of nicotinic acid (NA). We discovered that CD38 catalyzes synthesis of NAADP by exchanging the nicotinamide moiety of nicotinamide adenine dinucleotide phosphate (NADP(+)) for the NA group of nicotinic acid adenine dinucleotide (NAAD) inside endolysosomes of interleukin 8 (IL8)-treated lymphokine-activated killer (LAK) cells. Upon IL8 stimulation, cytosolic NADP(+)is transported to acidified endolysosomes via connexin 43 (Cx43) and gated by cAMP-EPAC-RAP1-PP2A signaling. CD38 then performs a base-exchange reaction with the donor NA group deriving from NAAD, produced by newly described endolysosomal activities of NA phosphoribosyltransferase (NAPRT) and NMN adenyltransferase (NMNAT) 3. Thus, the membrane organization of endolysosomal CD38, a signal-mediated transport system for NADP(+)and luminal NAD(+)biosynthetic enzymes integrate signals from a chemokine and cAMP to specify the spatiotemporal mobilization of Ca(2+)to drive cell migration.
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