Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP

Abstract

Edited by Mike Shipston Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two structurally distinct messengers that mobilize the endoplasmic and endolysosomal Ca 2؉ stores, respectively. Both are synthesized by the CD38 molecule (CD38), which has long been thought to be a type II membrane protein whose catalytic domain, intriguingly, faces to the outside of the cell. Accordingly, for more than 20 years, it has remained unresolved how CD38 can use cytosolic substrates such as NAD and NADP to produce messengers that target intracellular Ca 2؉ stores. The discovery of type III CD38, whose catalytic domain faces the cytosol, has now begun to clarify this topological conundrum. This article reviews the ideas and clues leading to the discovery of the type III CD38; highlights an innovative approach for uncovering its natural existence; and discusses the regulators of its activity, folding, and degradation. We also review the compartmentalization of cADPR and NAADP biogenesis. We further discuss the possible mechanisms that promote type III CD38 expression and appraise a proposal of a Ca 2؉-signaling mechanism based on substrate limitation and product translocation. The surprising finding of another enzyme that produces cADPR and NAADP, sterile ␣ and TIR motif-containing 1 (SARM1), is described. SARM1 regulates axonal degeneration and has no sequence similarity with CD38 but can catalyze the same set of multireactions and has the same cytosolic orientation as the type III CD38. The intriguing finding that SARM1 is activated by nicotinamide mononucleotide to produce cADPR and NAADP suggests that it may function as a regulated Ca 2؉-signaling enzyme like CD38.

The Circular Life of Human CD38: From Basic Science to Clinics and Back

“…It was initially thought that one characteristic shared by several nucleotide-metabolizing ectoenzymes was their ability to function in environments containing only trace amounts of the substrate and where the final product would be used prevalently inside the cell. This initial view was later refined, confirming that substrates and final products are not so topologically confined [ 29 , 30 ].…”

Neurodegeneration Caused by S1P-Lyase Deficiency Involves Calcium-Dependent Tau Pathology and Abnormal Histone Acetylation

“…It is well-established that mobilization of intracellular calcium stores is a universal signaling mechanism that cells employ for responding to a wide range of external stimuli [ 38 ]. Notably in SGPL1-deficient neurons, this stimulus is S1P [ 5 ].…”

Protein hyperacylation links mitochondrial dysfunction with nuclear organization

“…The copyright holder for this preprint this version posted October 23, 2020. ; https://doi.org/10.1101/2020.10.23.350892 doi: bioRxiv preprint 7 (precursors in de novo NAD + biosynthesis), but not nicotinamide (a precursor in the NAD + salvage pathway) (Hassa et al, 2006;Stein and Imai, 2012) (Figure 1D). Endogenous production of ADP-ribose from NAD + , known to occur via multiple mechanisms (Hassa et al, 2006), is correlated with increased expression NAD + glycohydrolases (Lee and Zhao, 2019) in the absence of other notable change in expression of NAD + -consuming and ADP-ribose generating enzyme activities ( Figure S1C). ADP-ribose has previously been described as an endogenous sirtuin inhibitor (Madsen et al, 2016), suggesting to us the possibility of sirtuin inhibition in SDHC KO cells.…”