− この都医学研セミナーは終了しました。 −
|世話人||田中 啓二 （東京都医学総合研究所 所長）|
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