Single‐Crystal‐to‐Single‐Crystal Installation of Ln₄(OH)₄ Cubanes in an Anionic Metallosupramolecular Framework

Postsynthetic installation of lanthanide cubanes into a metallosupramolecular framework via a single-crystal-to-single-crystal (SCSC) transformation is presented. Soaking single crystals of K6[Rh4Zn4O(l-cys)12] (K6[1]; l-H2cys=l-cysteine) in a water/ethanol solution containing Ln(OAc)3 (Ln3+=lanthanide ion) results in the exchange of K+ by Ln3+ with retention of the single crystallinity, producing Ln2[1] (2Ln) and Ln0.33[Ln4(OH)4(OAc)3(H2O)7][1] (3Ln) for early and late lanthanides, respectively. While the Ln3+ ions in 2Ln exist as disordered aqua species, those in 3Ln form ordered hydroxide-bridged cubane clusters that connect [1]6− anions in a 3D metal-organic framework through coordination bonds with carboxylate groups. This study shows the utility of an anionic metallosupramolecular framework with carboxylate groups for the creation of a series of metal cubanes that have great potential for various applications, such as magnetic materials and heterogeneous catalysts.This is the pre-peer reviewed version of the following article: N. Yoshinari, N. Meundaeng, H. Tabe, Y. Yamada, S. Yamashita, Y. Nakazawa, T. Konno, Angewandte Chemie. 2020, 132, 18204., which has been published in final form at https://doi.org/10.1002/ange.202008296.This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving

技術の人間化に基づいたサステナブルデザイン

本学研究所は、科学技術（工学）と芸術文化の融合をテーマに、人文・社会・自然にまたがる諸科学、および芸術的感性と表現技術を融合し、人類の生活文化を豊かにすることを目標としている。現在、人類の生存と地球環境を持続可能にする社会を作るために、自然環境の保全とともにヒトの適応能力に基づく生活環境の構築が注目されている。今年度は「技術の人間化に基づいたサステナブルデザイン」を課題として、下記の研究を実施した。 １．生体リズムを考慮した快適照明のデザイン ２．福祉とアートのコラボレーション ３．音楽を創るインターフェイス ４．ホスピタル・クラウンにみる笑いの芸術工学 ５．都市のなかのエコロジー：生態学的都市の見方 ６．農業分野に見るユニバーサルデザイン ～機能的で楽しい農作業着のデザインに関する調査研究～ ７．東日本大震災応急仮設住宅の実態調査 ８．デザインウォークinせんだい2011への参加 東日本大震災における神戸芸術工科大学の取り組みCreating a sustainable society that ensures the survival of humanity and the preservation of the global environment will require the achievement of a low-impact way of living based on a new set of values, and the elimination of the causal connection in modern civilization that holds that economic value is produced by the consumption of resources and energy. Design should not simply be understood as a narrow specialty, as it is currently viewed, but instead one that strengthens the relationship with various related domains and strives to create a sustainable society for the survival of humanity and the preservation of the global environment. Sustainable design based on the "humanization” of technology is being stressed as one way to resolve problems with humanity and in society. Particularly indispensable will be the construction of living environments that do not place excessive burden on the planet\u27s natural environment, and are based on the ability of human beings to adapt to natural, man-made and urban environments

TRAF6 Establishes Innate Immune Responses by Activating NF-κB and IRF7 upon Sensing Cytosolic Viral RNA and DNA

BACKGROUND:In response to viral infection, the innate immune system recognizes viral nucleic acids and then induces production of proinflammatory cytokines and type I interferons (IFNs). Toll-like receptor 7 (TLR7) and TLR9 detect viral RNA and DNA, respectively, in endosomal compartments, leading to the activation of nuclear factor kappaB (NF-kappaB) and IFN regulatory factors (IRFs) in plasmacytoid dendritic cells. During such TLR signaling, TNF receptor-associated factor 6 (TRAF6) is essential for the activation of NF-kappaB and the production of type I IFN. In contrast, RIG-like helicases (RLHs), cytosolic RNA sensors, are indispensable for antiviral responses in conventional dendritic cells, macrophages, and fibroblasts. However, the contribution of TRAF6 to the detection of cytosolic viral nucleic acids has been controversial, and the involvement of TRAF6 in IRF activation has not been adequately addressed. PRINCIPAL FINDINGS:Here we first show that TRAF6 plays a critical role in RLH signaling. The absence of TRAF6 resulted in enhanced viral replication and a significant reduction in the production of IL-6 and type I IFNs after infection with RNA virus. Activation of NF-kappaB and IRF7, but not that of IRF3, was significantly impaired during RLH signaling in the absence of TRAF6. TGFbeta-activated kinase 1 (TAK1) and MEKK3, whose activation by TRAF6 during TLR signaling is involved in NF-kappaB activation, were not essential for RLH-mediated NF-kappaB activation. We also demonstrate that TRAF6-deficiency impaired cytosolic DNA-induced antiviral responses, and this impairment was due to defective activation of NF-kappaB and IRF7. CONCLUSIONS/SIGNIFICANCE:Thus, TRAF6 mediates antiviral responses triggered by cytosolic viral DNA and RNA in a way that differs from that associated with TLR signaling. Given its essential role in signaling by various receptors involved in the acquired immune system, TRAF6 represents a key molecule in innate and antigen-specific immune responses against viral infection

Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling

Activation of the stimulator of interferon genes (STING) pathway by microbial or self-DNA, as well as cyclic dinucleotides (CDNs), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent proinflammatory disease by mechanisms that remain unknown. We demonstrate here that, after autophagy-dependent STING delivery of TANK-binding kinase 1 (TBK1) to endosomal/lysosomal compartments and activation of transcription factors interferon regulatory factor 3 (IRF3) and NF-κB, STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1), and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor AMP activated protein kinase (AMPK) and was elicited by CDNs generated by the cGAMP synthase, cGAS. Thus, although CDNs may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes

Ubiquitination of STING at lysine 224 controls IRF3 activation

Cytosolic DNA species derived from invading microbes or leaked from the nuclear or mitochondrial compartments of the cell can trigger the induction of host defense genes by activating the endoplasmic reticulum-associated protein STING (stimulator of interferon genes). Using a mass spectrometry-based approach, we show that after association with cyclic dinucleotides, delivery of Tank-binding kinase 1 to interferon regulatory factors (IRFs), such as IRF3, relies on K63-linked ubiquitination of K224 on STING. Blocking K224 ubiquitination specifically prevented IRF3 but not nuclear factor κB activation, additionally indicating that STING trafficking is not required to stimulate the latter signaling pathway. By carrying out a limited small interfering RNA screen, we have identified MUL1 (mitochondrial E3 ubiquitin protein ligase 1) as an E3 ligase that catalyzes the ubiquitination of STING on K224. These data demonstrate the critical role of K224 ubiquitination in STING function and provide molecular insight into the mechanisms governing host defense responses

Recurrent Loss of STING Signaling in Melanoma Correlates with Susceptibility to Viral Oncolysis

The innate immunoregulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells to stimulate antitumor T-cell immunity. Here, we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically, STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase, which generates STING-activating cyclic dinucleotides after binding cytosolic DNA species. Loss of STING function rendered melanoma cells unable to produce type I IFN and other immune cytokines after exposure to cytosolic DNA species. Consequently, such cells were highly susceptible to infection with DNA viruses including HSV1, a variant of which is being developed presently as a therapeutic oncolytic virus [talimogene laherparepvec (T-VEC)]. Our findings provide insight into the basis for susceptibility to viral oncolysis by agents such as HSV1. Cancer Res; 76(22); 6747-59. ©2016 AACR

Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis

Stimulator of interferon genes (STING) has been shown to be critical for controlling antiviral responses as well as anti-tumor adaptive immunity, but little is known regarding its regulation in human tumors. Here, we report that STING signaling is recurrently suppressed in a wide variety of cancers, including colorectal carcinoma. Loss of STING signaling impeded DNA damage responses accountable for generating key cytokines that facilitate tissue repair and anti-tumor T cell priming, such as type I interferons (IFNs). Correspondingly, defective STING function was also highly predictive of effectual DNA-virus-mediated oncolytic activity. Thus, impaired STING responses may enable damaged cells to evade host immunosurveillance processes, although they provide a critical prognostic measurement that could help predict the outcome of effective oncoviral therapy

Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis

Stimulator of interferon genes (STING) has been shown to be critical for controlling antiviral responses as well as anti-tumor adaptive immunity, but little is known regarding its regulation in human tumors. Here, we report that STING signaling is recurrently suppressed in a wide variety of cancers, including colorectal carcinoma. Loss of STING signaling impeded DNA damage responses accountable for generating key cytokines that facilitate tissue repair and anti-tumor T cell priming, such as type I interferons (IFNs). Correspondingly, defective STING function was also highly predictive of effectual DNA-virus-mediated oncolytic activity. Thus, impaired STING responses may enable damaged cells to evade host immunosurveillance processes, although they provide a critical prognostic measurement that could help predict the outcome of effective oncoviral therapy