DEFINITION
CD39 (Cluster of Differentiation 39) also known as Ectonucleoside triphosphatase diphosphohydrolase ENTPD1, is a membrane-bound protein that hydrolyzes ATP and ADP to AMP.
CD39 belongs to the ectonucleoside triphosphatase diphosphohy family and the other surface-located isoforms are:
ENTPD2
ENTPD3
ENTPD8
(The E-NTPDase family of ectonucleotidases: Structure function relationships and pathophysiological significance,2006)
Enzymatic cascade
THE GENE
CHEMICAL STRUCTURE AND IMAGES
CD39 is a putative 510-amino acid protein; structurally it is characterized by two transmembrane domains, a small cytoplasmic domain comprising the NH 2 and COOH-terminal segments, and a large extracellular hydrophobic domain.
In this domain there are the five highly conserved sequence domains known as apyrase conserved regions, abbreviated and termed ACR1 to ACR5, that are involved in the catalytic cycle, and they are common in all the isoforms. CD39 is firmly anchored to the membrane via two transmembrane domains that are important for maintaining catalytic activity and substrate specificity.
(The E-NTPDase family of ectonucleotidases: Structure function relationships and pathophysiological significance,2006)
Tridimensional structure
Functional modification
Since the surface-located ATP-hydrolyzing members of the NTPDase family pass through the endoplasmic reticulum and Golgi apparatus, the associated catalytic activity might abrogate ATP-dependent luminal functional processes. CD39 becomes catalytically active on reaching the cell surface and glycosylation reactions appear crucial. CD39 has 7 potential N-linked glycosylation sites and 11 Cys residues; the N-terminal intracytoplasmic domain is palmitoylated.
(The E-NTPDase family of ectonucleotidases: Structure function relationships and pathophysiological significance,2006)
PROTEIN AMINOACIDIC PERCENTAGE
CELLULAR FUNCTION
CD39 is expressed primarily on activated lymphoid cells. Also expressed in endothelial tissues.
Biological function
CD39 requires Ca 2+ or Mg 2+ ions in the millimolar range for maximal activity and is inactive in their absence.
It hydrolyzes nucleoside triphosphates including the physiologically active ATP and UTP, the hydrolysis rates for nucleoside diphosphates vary considerably between isoforms; CD39 hydrolyzes ATP almost directly to AMP with the transient production of minor amounts of free ADP.
(The E-NTPDase family of ectonucleotidases: Structure function relationships and pathophysiological significance,2006)
PATHWAY
CD39 IN IMMUNITY
CD39 is the first step in the metabolism of purine nucleotides, the second step is catalyzed by CD73, also known as ecto-5'-nucleotidase, that converts AMP to adenosine.
The purigenic system is one of them deputed to fine-tune immune cell functions; the other are for example cell-to-cell interactions, cytokine and chemokine secretion.
Puricgenic mediators, such as ATP and adenosine, are released into extracellular space in response to metabolic disturbances or other type of insults.
ATP is released by cell lysis or by other mechanisms including exocytosis of ATP-containing vesicles and through nucleotide-permeable channels.
CD39 converts ATP into AMP, and then CD73 dephosphorylates AMP into adenosine.
The receptors P1 and P2 expressed on the surface of immune cells are activated by adenosine and ATP respecticely, and mediate the immunomodulatory effects of purines.
(CD39 and CD73 in immunity and inflammation, 2013)
Immune system and lymphocytes
Given that the combination of CD39 and CD73 degrade ATP, ADP, and AMP to adenosine, they can be viewed as “immunological switches” that shift ATP-driven pro-inflammatory immune cell activity toward an anti-inflammatory state mediated by adenosine.
CD39 and CD73 are highly expressed on the surface of Regulatory T cell (Tregs) and have been increasingly used as markers of Tregs.
The catabolic activity of the CD39/CD73 axis is synchronized with the activation status of these cells.
Indeed, murine Tregs display increased CD39 activity only upon activation of their T-cell receptor (TCR), and this enzyme was found to be inactive in non-stimulated cells.
In addition, it was speculated that the enhanced CD39 activity allows the entrance of these cells into inflamed regions, where it reduces the extracellular level of ATP, thereby decreasing P2 receptor-mediated Treg cell death.
(CD39 and CD73 in immunity and inflammation, 2013)
(Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression, 2007)
CD39 IN DISEASES
Thrombotic diseases and Atherosclerosis
Endothelial cells express CD39 and they are actively involved in maintaining cardiovascular homeostasis.
The endothelial CD39/CD73 axis regulates hemostasis by converting the local environment from a prothrombotic ATP/ADP-rich state, to an antithrombotic, adenosine-rich environment. Accordingly, alterations in the expression and activity of CD39 or CD73 can give rise to disorders of thromboregulation.
(Ecto-nucleotidases of the CD39/NTPDase family modulate platelet activation and thrombus formation: Potential as therapeutic targets, 2006)
Vascular CD39 and CD73 regulate also several steps in the atherogenic process by governing purinergic signaling.
Apolipoprotein E (ApoE) knock-out mice, an experimental model of atherosclerosis, show decreased CD39 expression and activity in thoracic aorta, which correlates with the presence of atherosclerotic plaques.
It is speculated that the accumulation of ATP and ADP in ApoE knock-out mice may cause desensitization of P2 receptors, which in turn may contribute to decreased blood flow and may predispose an individual to atheroma formation.
(Impaired ATP-induced coronary blood flow and diminished aortic NTPDase activity precede lesion formation in apolipoprotein E-deficient mice, 2012)
Autoimmune diseases
Altered CD39 functions have also been shown to contribute to the pathophysiology of multiple sclerosis (MS). In patients affected by MS, a reduced number of CD39+ Treg cells was noted, in conjunction with defective control of Th17 cell proliferation, cells that are critically involved in the pathogenesis of this autoimmune disorder.
(CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis, 2009).
High expression of CD39 is found on CD4+ T cells isolated from the synovial fluid of patients with juvenile arthritis. There are two distinct populations of these cells: one that express Foxp3, and another that is Foxp3−.
Although these Foxp3− cells could hydrolyze ATP, they are unable to suppress the proliferation of T effector cells. In addition, they release pro-inflammatory cytokines (IL-2, IL-17, and IFN-γ) and probably contribute to joint inflammation.
But both the CD39+CD4+ T Foxp3+ and Foxp3−cells isolated from the joint have reduced CD73 expression and activity in comparison with circulating T cells, thereby the incomplete generation of adenosine may contribute to the inflammation of the joint.
(High expression of the ectonucleotidase CD39 on T cells from the inflamed site identifies two distinct populations, one regulatory and one memory T cell population, 2010)
Diabetes
A recent study has demonstrated that the susceptibility of mice to streptozotocin-induced diabetes, an experimental model of type 1 diabetes, was influenced by the level of expression of CD39.
CD39 knockout mice become diabetic faster than wild type animals.
The onset of diabetes in these animals was ascribed to a dysregulation of immunity rather than impaired glucose tolerance, as reconstitution of CD39 knockout mice with bone marrow from wild type animals reduced the incidence of diabetes.
By contrast, transgenic mice over-expressing CD39 were protected from streptozotocin-induced diabetes.
(The protective effects of CD39 over-expression in multiple low dose streptozotocin-induced diabetes in mice, 2013)
Cancer
Cancer and immune cells closely interact to generate an immunosuppressive environment by releasing immunomodulatory factors, which supports neoplastic growth and several studies have pointed to the critical task carried out by CD39 and CD73 in generating this immunosuppressed environment, characterized by increased adenosine levels, which promotes the development and progression of cancer.
(CD39 and CD73 in immunity and inflammation, 2013)
The CD39/CD73 complex participates in the process of tumor immunoescape, by:
- inhibiting the activation, clonal expansion, and homing of tumor-specific T cells (in particular, T helper and cytotoxic T cells),
- impairing tumor cell killing by cytolytic effector T lymphocytes,
- promoting, via pericellular generation of adenosine, a substantial component of the suppressive capabilities of Treg,
- enhancing the conversion of type 1 macrophages into tumor-promoting type 2 macrophages.
(ENTPD1/CD39 is a promising therapeutic target in oncology, 2013)
(Phenotypic and functional characteristics of CD4+ CD39+ FOXP3+ and CD4+ CD39+ FOXP3neg T-cell subsets in cancer patients, 2012)
Myeloid-derived suppressor cells (MDSCs), which are a recently discovered tumor infiltrating immune cell type, also appear to promote tumor growth by a CD39-mediated mechanism.
(Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma, 2012)
Sara Bulfamante
