Potential therapeutic applications of targeting signal-transducing adaptor protein-2 in autoimmune diseases

Adaptor proteins are involved in various immune responses via the modulation of many signaling pathways. Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein that contains typical domains such as the pleckstrin homology (PH) domain, Src homology domain, and a proline-rich region from the N-terminal region. In T cells, STAP-2 positively regulates T cell receptor (TCR)-mediated signaling by associating with CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) and lymphocyte-specific protein tyrosine kinase (LCK). Therefore, a peptide that inhibits the interaction between STAP-2 and CD3ζ ITAMs is likely to suppress TCR-mediated T cell activation, as well as T cell-mediated diseases. As expected, the peptide successfully inhibited the STAP-2/CD3ζ ITAM interaction and suppressed TCR-mediated signaling, cell proliferation, and interleukin (IL)-2 production in human/murine T cells. Furthermore, this inhibitor suppressed the pathogenesis of experimental autoimmune encephalomyelitis (EAE), which is widely recognized as a mouse model of multiple sclerosis, via the downregulation of T cell activation and infiltration of T helper (Th) 1/Th17 cells. These results suggest a new strategy for the treatment of multiple sclerosis and other immune diseases

Signal-transducing adaptor protein-2 has a nonredundant role for IL-33-triggered mast cell activation

Signal-transducing adaptor protein (STAP)-2 is one of the STAP family adaptor proteins and ubiquitously expressed in a variety types of cells. Although STAP-2 is required for modification of Fc epsilon RI signal transduction in mast cells, other involvement of STAP-2 in mast cell functions is unknown, yet. In the present study, we mainly investigated functional roles of STAP-2 in IL-33-induced mast cell activation. In STAP-2-deficient, but not STAP-1-deficient, mast cells, IL-33-induced IL-6 and TNF-alpha production was significantly decreased compared with that of wild-type mast cells. In addition, STAP-2-deficiency greatly reduced TLR4-mediated mast cell activation and cytokine production. For the mechanisms, STAP-2 directly binds to IKK alpha after IL-33 stimulation, leading to elevated NF-kappa B activity. In conclusion, STAP-2, but not STAP-1, participates in IL-33-induced mast cells activation

STAP-2 facilitates insulin signaling through binding to CAP/c-Cbl and regulates adipocyte differentiation

Abstract Signal-transducing adaptor protein-2 (STAP-2) is an adaptor molecule involved in several cellular signaling cascades. Here, we attempted to identify novel STAP-2 interacting molecules, and identified c-Cbl associated protein (CAP) as a binding protein through the C-terminal proline-rich region of STAP-2. Expression of STAP-2 increased the interaction between CAP and c-Cbl, suggesting that STAP-2 bridges these proteins and enhances complex formation. CAP/c-Cbl complex is known to regulate GLUT4 translocation in insulin signaling. STAP-2 overexpressed human hepatocyte Hep3B cells showed enhanced GLUT4 translocation after insulin treatment. Elevated levels of Stap2 mRNA have been observed in 3T3-L1 cells and mouse embryonic fibroblasts (MEFs) during adipocyte differentiation. The differentiation of 3T3-L1 cells into adipocytes was highly promoted by retroviral overexpression of STAP-2. In contrast, STAP-2 knockout (KO) MEFs exhibited suppressed adipogenesis. The increase in body weight with high-fat diet feeding was significantly decreased in STAP-2 KO mice compared to WT animals. These data suggest that the expression of STAP-2 correlates with adipogenesis. Thus, STAP-2 is a novel regulatory molecule that controls insulin signal transduction by forming a c-Cbl/STAP-2/CAP ternary complex

保管廃棄施設・Lにおける廃棄物容器の健全性確認; 計画立案から試運用まで

原子力科学研究所放射性廃棄物処理場では、放射性廃棄物を200Lドラム缶等の容器に収納して保管廃棄施設に保管している。保管している廃棄物(以下「保管体」という。)については、これまで保安規定等に基づく外観点検等を行うことで安全に管理している。しかし、屋外の半地下ピット式保管廃棄施設である保管廃棄施設・Lには、保管期間が40年以上に亘る保管体もあり、一部の容器(主としてドラム缶)では、表面のさびが進行しているものも確認された。このため、さらに長期に亘る安全管理を徹底するため、ピットから保管体を取り出し、1本ずつ容器の外観点検、汚染検査を行い、必要に応じて容器の補修や新しい容器への詰替え等を行う作業(以下「健全性確認」という。)を計画し、2019年4月に作業を開始した。本報告書は、健全性確認について、計画立案、課題の検討、試運用等の実績についてまとめたものである。We have been storing drums containing radioactive waste (radioactive waste packages) at waste storage facilities. We have been managing radioactive waste packages along traditional safety regulations. However, over 40 years has passed from a part of them were brought in pit-type waste storage facility L. Most of them are carbon steel 200 L drums, and surface of them are corroded. For better safety management, we started to take drums out from the pit and inspect them in FY 2019. After each inspection, we repair them or remove the contents of the drum and refill new drums if necessary. In this report, we will introduce the planning, the review of the plan, and the trial operation of this project