TAILIEUCHUNG - Báo cáo khoa học: GRAIL: a unique mediator of CD4 T-lymphocyte unresponsiveness

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 unre-sponsiveness. | 1FEBS Journal MINIREVIEW GRAIL a unique mediator of CD4 T-lymphocyte unresponsiveness Chan C. Whiting Leon L. Su Jack T. Lin and C. Garrison Fathman Department of Medicine Stanford University Stanford CA USA Keywords anergy cellcycle de-ubiquitinating enzymes DUBs E3 GRAIL RNF128 T-cell unresponsiveness tolerance ubiquitination ubiquitin-protein ligase Correspondence C. G. Fathman Department of Medicine Division of Rheumatology and Immunology Stanford University 269 Campus Drive West Stanford CA 94305 USA Fax 1 650 725 1958 Tel 1 650 723 7887 E-mail cfathman@ Received 31 March 2010 revised 29 June 2010 accepted 6 August 2010 doi 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. Introduction The ability to distinguish self from non-self is the most important requirement of the mammalian immune system. Central thymic and peripheral tolerance mechanisms have evolved to prevent lymphocyte-mediated self-destruction autoimmunity . Because thymic negative selection is not foolproof some autoreactive T cells escape negative selection. Peripheral tolerance mechanisms therefore need to be in place to maintain CD4 T-cell unresponsiveness to self. One important mechanism of peripheral tolerance that maintains CD4 T-cell unresponsiveness is anergy 1 2 . Anergic CD4 T cells fail to proliferate or to produce interleukin IL -2 following immunogenic stimulation. Based on the simplistic two-signal hypothesis full T-cell

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