• anergy;
  • cell cycle;
  • de-ubiquitinating enzymes (DUBs);
  • E3;
  • GRAIL;
  • RNF128;
  • T-cell unresponsiveness;
  • tolerance;
  • ubiquitination;
  • ubiquitin–protein ligase

GRAIL (gene related to anergy in lymphocytes, also known as RNF128), an ubiquitin–protein ligase (E3), utilizes a unique single transmembrane protein with a split-function motif, and is an important gatekeeper of T-cell unresponsiveness. Although it may play a role in other CD4 T-cell functions including activation, survival and differentiation, GRAIL is most well characterized as a negative regulator of T-cell receptor responsiveness and cytokine production. Here, we review the recent literature on this remarkable E3 in the regulation of human and mouse CD4 T-cell unresponsiveness.