NAD + ‐dependent internalization of the transmembrane glycoprotein CD38 in human Namalwa B cells

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CD38 is a bifunctional ectoenzyme, predominantly expressed on hematopoietic cells during differentiation, that catalyzes the synthesis (cyclase) and the degradation (hydrolase) of cyclic ADP-ribose (cADPR), a powerful calcium mobilizer from intracellular stores. Due to the well established role of calcium levels in the regulation of apoptosis, proliferation, and differentiation, the CD38/cADPR system seems to be a likely candidate involved in the control of these fundamental processes. CD38 is a type II transmembrane glycoprotein predominantly expressed on lymphocytes (1) but also present in a number of different cell types, including erythrocytes (2), hematopoietic progenitor cells (1), ␤-pancreatic cells (3), and cerebral (4) and cerebellar (5) neurons. Immunologically, CD38 can be defined as an "orphan receptor" since its binding by specific monoclonal antibodies directed against ectocellular epitopes elicits cellular responses in lymphocytes, including proliferation, activation, and rescue from apoptosis (6, 7). The signal transduction pathways implicated in these events are under study, but phosphorylation/dephosphorylation reactions of target kinases have been already demonstrated (6,8,9). Biochemically, CD38 is a bifunctional ectoenzyme that catalyzes the synthesis of cADPR 1 from NAD ϩ and also its hydrolysis to ADPR (2, 10). Cyclic ADPR is a potent Ca 2ϩ mobilizer from intracellular stores, in invertebrate as well as in mammalian cells (11), and its presence has been described in most mammalian tissues (12).The widespread tissue distribution of the CD38/cADPR system suggests its involvement in the control of pivotal Ca 2ϩ -controlled functions like contraction, secretion, cell proliferation/differentiation, and apoptosis. However, the topological paradox of the ectocellular production of an intracellular Ca 2ϩ mobilizer has raised questions on both the immunological and the biochemical functions of the CD38/cADPR system (13, 14). Cell death has been advocated as a means for local increase in extracellular NAD ϩ concentrations, sufficient to elicit the production of cADPR by the ectoenzyme CD38; in this respect, nanomolar concentrations of NAD ϩ have been detected in plasma (15) and cerebellar interstitial fluid (5) suggesting the theoretical possibility of an extracellular production of cADPR by CD38 "in vivo." In few selected cell systems, i.e. murine B-lymphocytes (10), rat cerebellar granule cells (5), and rat osteoclasts (16), extracellular, exogenously added cADPR was demonstrated to elicit functional responses in intact cells, but most reported effects of cADPR on cellular functions require permeabilization of target cells to ensure binding of the nucleotide to its intracellular receptor(s).Internalization of membrane-bound CD38, as observed in human Namalwa B-lymphocytes upon incubation with NAD ϩ or thiol reagents, is followed by an increase of intracellular cyclase activity (insensitive to protein synthesis inhibitors) and of intracellular cADPR concentration ([cADPR] i ) (17), suggesting that...

Section: Discussionsupporting

confidence: 67%

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confidence: 99%

Expression of CD38 Increases Intracellular Calcium Concentration and Reduces Doubling Time in HeLa and 3T3 Cells

Zocchi

Daga²,

Usai

et al. 1998

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“…3E). CD38 is known to be activated via its internalization from the plasma membrane through its association with phosphorylated MHCIIA by protein kinase G (23). To verify this notion, we treated J774A.1 macrophages with a specific MHCIIA inhibitor, blebbistatin (62), which completely blocked the IgG-opsonized latex beadinduced Ca 2ϩ signaling (Fig.…”

Section: Igg-opsonized Latex Beads Induce Fc␥r-mediated Phagocytosis mentioning

confidence: 99%

“…It has also been suggested that CD38 is internalized once activated via endocytosis, thus allowing its catalytic site to interact with intracellular substrates (19 -21). This internalizing event has been observed in many different cellular responses where cADPR production is shifted from the surface to inside the cell (22,23). It has been suggested that the internalization mechanism is mediated by non-muscle myosin heavy chain IIA (MHCIIA), where both CD38 and MHCIIA were found to be associated in activated lymphokine-activated killer cells (24).…”

mentioning

confidence: 99%

The Role of CD38 in Fcγ Receptor (FcγR)-mediated Phagocytosis in Murine Macrophages

Kang

Park

Kim

et al. 2012

Background: Ca 2ϩ signaling in Fc␥R-mediated phagocytosis is unclear. Results: We show that Fc␥R-mediated phagocytosis requires the production of cyclic ADP-ribose by CD38. Conclusion: CD38 plays a crucial role for Ca 2ϩ signaling in Fc␥R-mediated phagocytosis. Significance: This study provides new perspectives in immune defense and can help shed light on developing novel methods or drugs for manipulating bacterial infections.

“…cADPR has also been shown to augment the proliferative response of activated murine B lymphocytes (5), as well as to mediate the Ca 2ϩ release associated with ATP-activated potassium currents in alveolar macrophages (10), suggesting that cADPR may function as a signaling second messenger in multiple hematopoietic cell types. Although the physiological ligand for CD38 has yet to be identified, CD38 was reported to undergo internalization through non-clathrincoated endocytic vesicles upon incubating cells with thiol compounds or NAD (11). The mechanism by which endocytic vesicles can generate cADPR was suggested by the demonstration that the CD38-catalyzed conversion of NAD to cADPR can be achieved by the influx of cytosolic NAD into the endocytic vesicles and the cADPR into the cytosol for subsequent Ca 2ϩ signaling (12).…”

mentioning

confidence: 99%

Interaction of Two Classes of ADP-ribose Transfer Reactions in Immune Signaling

Han¹,

Cho²,

Kim³

et al. 2000

CD38 is a bifunctional ectoenzyme predominantly expressed on hematopoietic cells where its expression correlates with differentiation and proliferation. The two enzyme activities displayed by CD38 are an ADP-ribosyl cyclase and a cyclic adenosine diphosphate ribose (cADPR) hydrolase that catalyzes the synthesis and hydrolysis of cADPR. T lymphocytes can be induced to express CD38 when activated with antibodies against specific antigen receptors. If the activated T cells are then exposed with NAD, cell death by apoptosis occurs. During the exposure of activated T cells to NAD, the CD38 is modified by ecto-mono-ADP-ribosyltransferases (ecto-mono-ADPRTs) specific for cysteine and arginine residues. Arginine-ADP-ribosylation results in inactivation of both cyclase and hydrolase activities of CD38, whereas cysteine-ADP-ribosylation results only in the inhibition of the hydrolase activity. The arginine-ADPribosylation causes a decrease in intracellular cADPR and a subsequent decrease in Ca 2؉ influx, resulting in apoptosis of the activated T cells. Our results suggest that the interaction of two classes of ecto-ADP-ribose transfer enzymes plays an important role in immune regulation by the selective induction of apoptosis in activated T cells and that cADPR mediated signaling is essential for the survival of activated T cells.