平成28年度 医学研セミナー

Linear Ubiquitin Chains: NF-κB Activation, Cell Death, and Beyond

− この都医学研セミナーは終了しました。 −

演者 岩井 一宏
京都大学・大学院医学研究科・細胞機能制御学 教授
会場 東京都医学総合研究所 2階講堂
日時 平成28年11月29日(火)15:20~16:40
世話人 田中 啓二 (東京都医学総合研究所 所長)
参加自由 詳細は下記問合せ先まで
お問い合わせ 研究推進課 普及広報係


Linear ubiquitin chains, which are generated by conjugation of the carboxyl group of a ubiquitin monomer to the α-amino group of the first Met of another ubiquitin, are involved in the activation of the NF-κB transcription factor and cell death regulation. Linear ubiquitin chains are exclusively generated by the LUBAC ubiquitin ligase complex, which is composed of catalytic HOIP and two accessory HOIL-1L and SHARPIN subunits.

Deletion of SHARPIN leads to chronic inflammation of various organs including skin observed in mice because of the destabilization of LUBAC. Further reduction of LUBAC by heterozygous deletion of HOIL-1L in SHARPIN null mice deteriorated inflammatory symptoms. We then dissected mechanism nderlying stable trimetric LUBAC formation. In addition to previously identified HOIP-HOIL-1L and HOIP-SAHRPIN interactions, we found novel interaction between HOIL-1L and SHARPIN and inhibition of HOIL-1L-SHARPIN interaction drastically reduced the amount of LUBAC. Considering the involvement of LUBAC-mediated linear ubiquitination in oncogenesis of some form of B cell lymphoma, inhibition of HOIL-1L-SHARPIN interaction might provide an alternative strategy for the treatment of the disease.

As deletion of the catalytic HOIP subunit results in embryonic lethality because of the complete loss of the LUBAC activity, graded reduction of the ligase activity can be achieved by conditional genetic ablation of SHARPIN or HOIP. Considering the involvement of LUBAC in inflammatory diseases, we dissected the roles of LUBAC in Treg cells. We unexpectedly found that deletion of SHARPIN or HOIP displays quite different systemic autoinflammatory symptoms although both phenotypes are provoked in T cell dependent manner. Our results shed a light on the autoimmune diseases caused by Treg dysfunction. Treg dysfunction potentially exhibits a wide range of inflammatory characteristics and that functional balance between self-reactive T and immunosuppressive Treg cells appears to determine pathological manifestations