The control of MHC class I by viral and cellular E3 ligases. (360G-Wellcome-084957_Z_08_Z)

Regulation of cell surface receptors is essential to maintain cell homeostasis, especially following receptor stimulation to limit the duration and intensity of signalling. Receptor ubiquitination is an important mechanism for regulating expression of critical immunoreceptors. The K3 and K5 viral E3 ligases ubiquitinate cell surface class I, promoting its endolysosomal degradation, and we showed an absolute requirement for lysine-63 linked polyubiquitination of class I for its downregulation. Th ese viral genes accelerate a constitutive pathway of class I regulation. Continued studies on K3 and K5 will further define this receptor regulation pathway. Biochemical inhibitors of class I ubiquitination, and RNAi screens will identify the cellular ligase(s) responsible for class I ubiquitination, and establish the role of lysine-63 linked polyubiquitination in regulating class I and other immunoreceptors. Investigations into the viral ligases identified an unrecognised family of cellular lig ases the MARCH proteins, whose expression downregulates surface receptors. We have developed screening and mass spectrometry-based techniques, as well as MARCH9 knockout mice, to identify the substrates and function of these proteins. Biochemical studies on the regulation and expression of MARCH9, together with an analysis of MARCH9 deficient mice will determine the physiological role of the MARCH9 E3 ligase in immunoreceptor regulation.