GRAIL targets CDC37 to maintain CD4 T cell unresponsiveness (50.9)

Abstract It has long been appreciated that CD4 T cells are held in G1/S cell cycle arrest. How this is initially achieved, and then lost upon activation, is not well understood. Recent studies from our lab have demonstrated that the E3 ligase, GRAIL (gene related to anergy in lymphocytes, also known as RNF128), is expressed only in late stage QA2 positive thymocytes upon their exit from the thymus, and that its expression holds CD4 T cells in cell cycle arrest. GRAIL is not only expressed in late stage thymic migrants, but in resting CD4 T cells as well as in anergic CD4 T cells suggesting that GRAIL might be involved in holding CD4 T cells in cell cycle arrest. Using a novel E3 substrate screen, we identified cdc37 (a G1-specific cyclin) as a target of GRAIL mediated ubiquitination. Consistent with this idea, GRAIL expression leads to diminished cdc37 expression and maintained cell cycle arrest upon activation. Inversely, primary CD4 T cells lacking GRAIL have higher levels of cdc37 compared to wildtype T cells in resting conditions and allow full activation with TCR stimulation in the absence of costimulation. These data suggest that GRAIL ubiquinates and targets cdc37 for degradation and thus, maintains CD4 T cells in G1/S cell cycle arrest. These data also highlight a role for cdc37 in GRAIL-mediated cell cycle regulation and CD4 T cell proliferation. The activated CD4 T cells reacquire GRAIL expression and return to the resting G1/S interphase by unknown mechanisms.