GRAIL: A unique mediator of CD4 T-lymphocyte unresponsiveness

Department of Medicine, Stanford University, Stanford, CA 94305, USA.
FEBS Journal (Impact Factor: 4). 10/2010; 278(1):47-58. DOI: 10.1111/j.1742-4658.2010.07922.x
Source: PubMed


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.

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    • "Mice deficient in GRAIL are resistant to immune tolerance induction and are more susceptible to autoimmune diseases than wild-type mice (Whiting et al., 2011). GRAIL may mediate anergy induction by down-regulating the expression of CD3, CD40L, CD151, and CD81, as well as affecting rearrangement of the actin cytoskeleton (Whiting et al., 2011). Moreover, Lin et al. (2009) suggested that GRAIL expressed in quiescent naïve CD4 T cells has a functional role in inhibiting cell proliferation, and its degradation is required to allow T cell proliferation. "
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    • "oles for membrane trafficking in biology , transmembrane E3 ubiquitin ligases are found in various biological systems from plants to animals . For instance , in humans , RNF128 , also called GRAIL , down - regulates T - cell activity by using its extracellular PA do - main to target certain receptors for endocytosis ( Lineberry et al . 2008a , b ; Whiting et al . 2011 ) . Indeed , Dali analysis reveals that the RNF43 PA domain shares structural similarities with GRAIL / RNF128 ( Z - score = 11 . 4 ) , sug - gesting an evolutionarily conserved domain architec - ture . The RNF43 PA domain consists of seven b strands ( forming a twisted b sheet ) and three peripheral a helices . Of note , the curved b3 "
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