講師: Kazuhiro Iwai, M.D., Ph.D.
Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University
演題: Linear ubiquitination: Unexpected regulation and involvement in immunological disorders
Linear (M1-linked) ubiquitin chains, which are exclusively generated by the LUBAC
ubiquitin ligase complex, played crucial roles in inflammatory signaling by inducing NF-kB
activation and suppressing programmed cell death including apoptosis and necroptosis.
LUBAC is composed of three subunits and the HOIP subunit has the catalytic center for
linear ubiquitination. The HOIL-1L subunit also has the E3 ligase center, however, precise
function of HOIL-1L E3 has not been elucidated. We unexpectedly found that HOIL-1L E3
attenuates LUBAC function by conjugating mono-ubiquitin to all three LUBAC subunits.
Introduction of E3-defective HOIL-1L mutants augments NF-kB activation and suppresses
programmed cell death. We are now dissecting roles of linear ubiquitination in
immunological disorders and found that augmented LUBAC activity appears causative to
some human autoimmune diseases. Our current progress will be presented in this lecture.