CD38 is a type II membrane protein, originally identified as a cell surface differentiation marker in B lymphocytes, and later found to be expressed ubiquitously [1] [2] . In fact, CD38 is a versatile molecule with big ambitions. Although early studies revealed that CD38 serves as a differentiation antigen on cell surface, multiple studies have indicated a more diverse role for CD38 in many physiological and pathological processes, including Ca²⁺ signaling, autophagy, tumorigenesis, autism spectrum disorder (ASD), richter syndrome, acquired immune deficiency syndrome (AIDS) and type II diabetes [2] - [14] .

As a transmembrane protein, human CD38 is a 46-kDa glycoprotein, which consists of three conserved regions: a short N-terminal topological domain (NTD, residues 1 - 21), a single transmembrane helix domain (TMD, residues 22 - 44) and a long C-terminal catalytic domain (CCD, residues 45 - 300) (Figure 1). Some key amino residues in C-terminal catalytic region are responsible for nucleosidase activity of CD38. Mutations of the three residues W125F, W189G and E226G, affect the catalytic activity and subsequent calcium signaling [13] . CD38 catalyzed synthesis of cADPR, which increased intracellular Ca²⁺ and resulted in microglial activation and activation-induced cell death [14] . Moreover, CD38 contains some variations in single nucleotide that occur at specific sites in the genome, called single-nucleotide polymorphisms (SNPs), which have been used in genome-wide association studies (GWAS) as a key marker in gene mapping related to human diseases. The SNP position of CD38 at residues R140 (corresponding to rs1800561) is closely related to ASD or type II diabetes [9] [11] . Another SNP site rs6449182 at P184 is associated with richter syndrome [9] [10] [11] . Besides, the three disulfide bonds of CD38 are sponsored by cysteine residues between C160 and C173, C254 and C275, C278 and C296 [13] . The N- linked glycosylation modifications are usually occurring at four asparagine residues N100, N164, N209 and N219 [15] . These disulfide bonds and glycosylation modifications might play important roles in the topology of CD38 [4] .

Generally speaking, intracellular Ca²⁺ oscillation arise either from its release

from intracellular stores, such as endoplasmic reticulum (ER), endolysosome and mitochondria, or by modulating Ca²⁺ channels at the plasma membrane, including voltage-dependent calcium channels (VDCCs), Na⁺/Ca²⁺ exchanger (NCX), plasma membrane calcium-transporting ATPases (PMCAs), cyclic nucleotide-gated ion channels (CNGCs), α-amino-3-hydroxy-5-methyl-4-isoxazo- lepropionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NM- DAR) [2] [16] .

As we known, Streb et al. discovered the Ca²⁺-mobilizing activity of inositol 1,4,5-triphosphate (IP₃), which targets IP₃ receptor (IP₃R) in ER and stimulates ER-Ca²⁺ release [2] [17] . In addition to IP₃, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are also identified as important intracellular Ca²⁺ messengers, which elicit intracellular Ca²⁺ flux from either ER or endolysosome. As a multifunctional enzyme, CD38 is responsible for the synthesis of cADPR and NAADP from NAD and NADP, respectively [2] [3] . Besides, CD38 also plays a critical role in the degradation of NAADP by hydrolyzing NAADP to ADP-ribose 2’-phosphate [18] . It is known that both IP₃ and cADPR trigger Ca²⁺ release from the ER via the IP₃R and ryanodine receptors (RYR), respectively. However, the other potent Ca²⁺-mobilizing messenger NAADP drive Ca²⁺ flux from the endolysosomal pools by targeting the two-pore channels (TPCs) or transient receptor potential mucolipin-1 (TRPML1) [3] [19] [20] . Intriguingly, the CD38/NAADP-mediated lysosome Ca²⁺ signaling have been shown to participate in the physiological regulation of cell functions or activities, such as autophagy and apoptosis [21] . Cumulating evidence has suggested that autophagosomes trafficking and fusion with lysosomes is a NAADP/ Ca²⁺ signaling dependent process [22] . Thus, modulating the production of NAADP in cells by CD38 may be play important roles in lysosomal functions, especially autolysosomes formation and autophagic contents elimination.

Most lines of evidence support the positive regulation of CD38 in autophagy. Cumulating evidence has suggested that lysosome trafficking and fusion to autophagosomes is positively modulated by NAADP via CD38 enzymatic activity [19] [42] . Deficiency of CD38 resulted in a defective autophagic event in coronary arterial media of mice [22] [43] . Inhibition of CD38 by CD38 shRNA or nicotinamide leads to accumulation of p62 and autophagosomes, suppressing lysosome fusion to autophagosomes [44] . Moreover, in indolocarbazole induced

cell autophagy, CD38 expression and the LC3-II/LC3-I ratio are significantly elevated in response to ZW2-1 [45] . Subsequent studies showed that enzymatic activity of CD38 to produce NAADP plays an essential role in the following breakdown of the autophagic contents [19] . When nucleosidase activity of CD38 is disrupted or NAADP production is decreased, the formation of autolysosomes and degradation of autophagic vesicles also become impaired, which promotes cell dedifferentiation, proliferation and growth [19] . Besides, NAADP is also reported to increase acidic vesicular organelle formation and the expression levels of LC3II and Beclin-1 [46] . It is known that ROS promote autophagy maturation by regulating dynein-mediated autophagosomes trafficking [47] . High glucose induced ROS production results in the activation of dynein ATPase, which further triggers autophagosomes trafficking and fusion with lysosomes [47] . Moreover, antagonism of NAADP mediated Ca²⁺ signaling with NED-19 and pyridoxalphosphate-6-azophenyl-2’,4’-disulfonic acid (PPADS) eliminated ROS- evoked lysosomes Ca²⁺ flux and dynein activation [47] .

In contrast, CD38 is also involved in inhibition of autophagy. Some lines of evi-

dence indicate that CD38 is a autophagy suppressor. Deficiency of CD150 is associated with increased expression levels of CD38 and inhibited phosphorylation of p38, JNK1/2, Bcl-2 and autophagic flux [7] . Moreover, CD38 deficiency immature hematopoietic progenitors show a higher autophagic flux as shown by analysis of LC3-II and p62 levels, as well as flow cytometry-based autophagic vesicle quantification [48] . NAADP as a potent Ca²⁺ mobilizing messenger, which targets the TRPMLs or TPCs and triggers Ca²⁺ release from the endolysosomal stores [19] . As we known, the members of the TRPML constitute a family of evolutionarily conserved cation channels that play crucial roles in endolysosomal vesicles [20] [49] . TRPMLs localize to endolysosomes and facilitate Ca²⁺-de- pendent fusion between autophagosomes and lysosomes resulting in lysosomal degradation of autophagic material [20] . It is known that TPCs have recently emerging as the targets for NAADP, which are crucial for appropriate basal and induced autophagic flux in cardiomyocytes [50] . For instance, overexpression of TPC2 in vitro suppressed autophagosomal-lysosomal fusion, thereby resulting in the decreasing levels of LC3-II and p62 and the accumulation of autophagosomes, suggesting that inhibition of autophagy progression by TPC2 [39] [41] . Thus, NAADP and its receptors (TRPMLs or TPCs) in lysosome may play crucial roles in lysosomal functions and subsequent autophagy events.

It is well established that intracellular Ca²⁺ is one important regulators of autophagy [21] . Firstly, intracellular Ca²⁺-mobilization stimulates calmodulin (CaM), ERK and PKCθ signaling, thereby mediating autophagy progression. Of note, overexpression of leucine-rich repeat kinase 2 (LRRK2) stimulates an increase in autophagy initiation through Ca²⁺-dependent activation of a CaMKKβ/adeno- sine monophosphate (AMP)-activated protein kinase (AMPK) pathway [51] [52] . Moreover, Ca²⁺ also inhibits autophagy by promoting mitochondria ATP, which inhibits CaMKKβ/AMPK pathway [21] . Thus, CD38 triggers intracellular Ca²⁺ flux from ER and lysosome can also result in opposite outcomes of autophagy directly, depending on multiple stimuli and the different cellular state. As illustrated in Figure 3, CD38 catalyzes the synthesis of cADPR and NAADP from NAD and NADP, respectively. These two messengers target to RYR and TPC or TRP-ML1, modulating ER-Ca²⁺ signaling and lysosome-Ca²⁺ signaling, respectively. On the one hand, increasing of intracellular Ca²⁺ leading to activation of dynein ATPase, ERK, PKCθ or cAMKKβ/AMPK signaling pathways, thus facilitates the formation of autolysosome. On the other hand, Ca²⁺ releases promoting ATP synthesis in mitochondria and AMPK inhibition, leading to suppression of mTOR and autophagy. In addition, releasing of Ca²⁺ from lysosome by TPC2 or TRPML-1 have been suggested to inhibit Rab7 and alkalinizing lysosomal pH, thereby resulting suppression of autophagosomal-lysosomal fusion, accumulation of autophagosomes in cytosol and subsequently autophagy impairment.

Indeed, CD38 is involved in various stimuli induced autophagy. FasL has been shown to significantly increase NAADP production and intracellular Ca²⁺ flux in CD38 overexpressed mice [53] . In experimental autoimmune myocarditis mouse model, IL-17 promote B cell autophagy by controlling B-lymphocyte- induced maturation protein-1 (Blimp-1) expression and CD38⁽⁺⁾ CD138⁽⁺⁾ B cell percentages [54] . Not surprisingly, CD38 is possibly implicated in autophagy by variety of mechanisms. Lu et al. demonstrated that Vacuolin-1 suppress general endosomal-lysosomal degradation by decreasing V-ATPase activity to enhance lysosomal pH in HeLa cells [38] . Of interest, in addition to CD38, other NAD⁺ dependent enzymes, such as silent information regulator 2-related enzymes (Sirtuins) and the polymerase (ADP-ribose) polymerases (PARPs), act as the key mediators of macro autophagocytotic cell death [55] [56] . There is a potential crosstalk among CD38, Sirtuins and PARPs in autophagic cell death and survival pathways [56] .

Taken together, there are several potential mechanisms of CD38 in autophagy, including 1) mobilizing intracellular Ca²⁺ release by producing cADPR and NAADP, 2) affecting the functions of lysosome by regulating the activity of lysosome related proteins, e.g. TPC2, Vacuolin-1, and 3) crosstalking with other NAD⁺-dependent enzymes, e.g. Sirtuins, PARPs. Thus, continuing to study the mechanism of CD38 and its related proteins in autophagy is very interesting works.