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CD38 controls ADP-ribosyltransferase-2-catalyzed ADP-ribosylation of T cell surface proteins

J Immunol. 2005 Mar 15;174(6):3298-305. doi: 10.4049/jimmunol.174.6.3298.

Abstract

ADP-ribosyltransferase-2 (ART2), a GPI-anchored, toxin-related ADP-ribosylating ectoenzyme, is prominently expressed by murine T cells but not by B cells. Upon exposure of T cells to NAD, the substrate for ADP-ribosylation, ART2 catalyzes ADP-ribosylation of the P2X7 purinoceptor and other functionally important cell surface proteins. This in turn activates P2X7 and induces exposure of phosphatidylserine and shedding of CD62L. CD38, a potent ecto-NAD-glycohydrolase, is strongly expressed by most B cells but only weakly by T cells. Following incubation with NAD, CD38-deficient splenocytes exhibited lower NAD-glycohydrolase activity and stronger ADP-ribosylation of cell surface proteins than their wild-type counterparts. Depletion of CD38(high) cells from wild-type splenocytes resulted in stronger ADP-ribosylation on the remaining cells. Similarly, treatment of total splenocytes with the CD38 inhibitor nicotinamide 2'-deoxy-2'-fluoroarabinoside adenine dinucleotide increased the level of cell surface ADP-ribosylation. Furthermore, the majority of T cells isolated from CD38-deficient mice "spontaneously" exposed phosphatidylserine and lacked CD62L, most likely reflecting previous encounter with ecto-NAD. Our findings support the notion that ecto-NAD functions as a signaling molecule following its release from cells by lytic or nonlytic mechanisms. ART2 can sense and translate the local concentration of ecto-NAD into corresponding levels of ADP-ribosylated cell surface proteins, whereas CD38 controls the level of cell surface protein ADP-ribosylation by limiting the substrate availability for ART2.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADP Ribose Transferases / metabolism*
  • ADP-ribosyl Cyclase / antagonists & inhibitors
  • ADP-ribosyl Cyclase / genetics
  • ADP-ribosyl Cyclase / metabolism*
  • ADP-ribosyl Cyclase 1
  • Adenosine Diphosphate Ribose / metabolism
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Immunomagnetic Separation
  • In Vitro Techniques
  • L-Selectin / metabolism
  • Membrane Glycoproteins
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NAD / analogs & derivatives
  • NAD / metabolism
  • NAD / pharmacology
  • Phosphatidylserines / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*

Substances

  • Antigens, CD
  • Membrane Glycoproteins
  • Membrane Proteins
  • Phosphatidylserines
  • NAD
  • L-Selectin
  • Adenosine Diphosphate Ribose
  • ADP Ribose Transferases
  • Art2a protein, mouse
  • Art2b protein, mouse
  • ADP-ribosyl Cyclase
  • Cd38 protein, mouse
  • ADP-ribosyl Cyclase 1