Millennium reviewHuman CD38: a (r)evolutionary story of enzymes and receptors☆
Introduction
Understanding the CD38 receptor system has been an unfolding odyssey which lasted over two decades. The current view of this receptor system results from combined observations from several laboratories and clinics working on different aspects of the molecule.
Human CD38 was initially defined by Reinherz and Schlossman in 1980 in their pioneering studies of thymocyte and T lymphocyte differentiation antigens [1]. Several monoclonal antibodies (mAbs) later raised against CD38 have been clustered since the Third International Workshop on Human Differentiation Antigens in 1987. The turning point in the study of the molecule was marked by the finding of a structural and functional similarity with a soluble enzyme purified from the mollusc Aplysia californica [2]. As a consequence, scientists of a biochemical bent focused their attention on the catalytic activities of CD38, while the immunologists adopted a new perspective from which to view the molecule as a surface receptor. The convergence of these two approaches will provide a unifying view of the biology and functions of CD38.
This laboratory stumbled across CD38, while raising mAbs against HLA Class II products [3]. The A10 mAb (and its subclone IB4, a hybridoma selected for its high antibody production) was used for an initial structural and functional analysis of the molecule [4], [5]. This mAb was also able to induce modulatory effects on the expression of surface activation markers in T, B, NK and plasma cells [6]. Additionally, A10 mAb induced proliferation in several cells analyzed and the phenomenon was accessory cell- and interleukin-(IL)-2-dependent. The effects induced by A10 mAb suggested that CD38 was involved in the activation of lymphoid and myeloid cells, although understanding of its mechanisms was murky at best. The finding of a physical and functional membrane association between CD38 and the main signaling complexes of T, B and NK cells [7] represented a step forward in defining the signals mediated by CD38. The resulting view was of CD38 as a promiscuous receptor, which took advantage of the machinery of dedicated signaling receptors. The presence of specialized compartments in the plasma membrane containing clusters of co-modulating structures, including different receptors involved in the transduction of extracellular signals, significantly supported this view [8], [9]. This scenario was further refined by the identification of a cell surface ligand for CD38 [10]. Thus, CD38 was ushered into the world of adhesion molecules, and was found to be involved in heterotypic cell interactions, both in open environments (e.g. T lymphocytes interacting with endothelial cells in blood vessels) [11] and in closed ones (e.g. immature hemopoietic cells interacting with stromal cells in the bone marrow and mature residential T and B cells).
While immunologists were busy defining its signals and ligands, biochemists concentrated on its enzymatic aspects and eventually revealed the complete range of catalytic functions of the molecule [12], [13], [14]. Even as an enzyme, CD38 may be considered promiscuous, as it apparently works in strict collaboration with a network of surface enzymes involved in the metabolism of NAD+ [15].
A final major contribution was made as a result of a thorough genetic analysis which began more than a decade ago. The gene coding for CD38 was assigned to chromosome 4 by using a conventional approach of somatic cell genetics (i.e. the OKT10 mAb was used to detect expression of CD38 on murine×human somatic hybrids) [16]. This work was completed a few years ago with the identification of a CD38 gene cluster which encodes a family of surface molecules. These CD38 family members share phylogenetic origins, structural conformation and biological functions [17](Fig. 1).
Section snippets
The proteins and the genes
The protein encoded by the CD38 gene is a type II single chain transmembrane molecule displaying a Mr of 45 kD. The architecture of the molecule consists of three regions: intracellular (20 amino acids), transmembrane (23 amino acids) and extracellular (257 amino acids). The oligosaccharide residues in the latter region account for ∼25% of the apparent mass [4].
In addition to the canonical 45 kD structure, experiments showed that the molecule may exist in a soluble form present in biological
Distribution of CD38 and CD157
Distribution studies on CD38 suffered from a bias determined by the context of its initial identification. The results obtained by the hematological/immunological community during the 1980s and early 1990s labeled CD38 expression as discontinuous, as it was not restricted to a differentiation state or to activation only [31]. Paradigmatic in this respect is the situation in the B cell compartment, where the molecule is expressed by precursor cells inhabiting the bone marrow and by terminally
The enzymatic activities of the CD38 family
The first evidence for the enzymatic activity of CD38 was reported in the murine model in 1993 [12] and was later confirmed in humans [47]. The experimental information gathered in these 7 years are an invitation to revisit the concept of CD38 as an enzyme [48]. The first point that needs to be stressed is that CD38 should no longer — or not only — be considered as an ecto-enzyme (a protein which harbors its catalytic site outside the plasma membrane), but as a full-fledged enzyme. Indeed, several
The receptorial activities of the CD38 family
The inclusion of CD38 in the family of ecto-enzymes did not prevent cell biologists from considering the possibility that CD38 may regulate important cellular functions by interacting with surface-bound receptors. This inference was in part derived from the molecule's discontinuous pattern of expression, its modulation upon physiological stimuli and its expression in pathological conditions. We gave preference to the model of a cell surface counter-receptor, as suggested by the expression of
Lessons from diseases
Vital immune mechanisms are being revealed by the study of diseases: as a direct consequence, an increasing number of the CD family members — once considered orphan receptors — are now implicated in the pathogenesis of diseases or as markers of their progression or prognosis. Experience accumulated over the past decade indicates that CD38 is no exception. Indeed, the molecule has been connected to HIV infection, leukemias, myelomas, solid tumors, type II diabetes mellitus and bone metabolism, as
Conclusions
This review focused on the events that have led to the development of the present model of the CD38 family. Although studies on CD38 have been ongoing since the early 1980s, the most rapid advances have occurred during the past decade. During this time, reports on the genetics, the structure and the biological functions of CD38 concurred to portray a dual-function protein which may perform independently as an (ecto)-enzyme and as an adhesion receptor molecule. Moreover, CD38 was found to have a
Acknowledgements
This work was supported by grants from AIRC, Telethon, Special Projects ‘AIDS’ (Istituto Superiore di Sanità, Roma, Italy) and ‘Biotechnology’ (CNR/MURST, Roma, Italy) and MURST (Cofinanziamento). The Compagnia di Sanpaolo, Cariverona and Ghirotti Foundations and Regione Piemonte provided valuable financial contributions. Silvia Deaglio is a student of the Postgraduate School of Medical Oncology, University of Torino Medical School, Torino, Italy. All authors contributed equally to this work.
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All co-authors contributed equally to this effort.