Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway
Jianwen ChenBao ZhaoHong DongTianliang LiCheng XiangWang GongJing WangJunran ZhangGang XinYanbao YuYu L. LeiJennifer D. BlackZihai LiHaitao Wen
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The O -GlcNAc transferase (OGT) is an essential enzyme that mediates protein O -GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O -GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent hosts by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT ( Ogt −/− ) caused a marked reduction in tumor growth in both syngeneic tumor models and a genetic colorectal cancer (CRC) model induced by mutation of the Apc gene ( Apc min ). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt −/− cancer cells restored tumor growth, and this correlated with impaired CD8 + T cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor cell-intrinsic mechanism to repress antitumor immunity.白色レグホーン種産卵鶏の卵管子宮部のCytosolおよび細胞核画分のいずれにおいてもエストロジェンに対する選択的結合性(結合特異性)と結合飽和性とが認められた.結合物質の解離定数(Kd)は Cytosolおよび細胞核画分のいずれにおいても10-10Mのオーダーの値であり,NBS max(最大結合部位数)は Cytosolにおいては蛋白質1mg当り10-14～10-15molesであり,細胞核画分においてはDNA 1μg当り10-16～10-15molesであった.この結合物質のKd値は産卵鶏と休産鶏とで差がなく,NBS maxは産卵鶏の方が大であった.休産鶏にエストラジオール•17βを投与すると Cytosolおよび細胞核画分のKd値には顕著な変化は認められないが,NBS max値はCytosolにおいては減少し,細胞核画分においては増加した.上記の結果より,鶏の卵管子宮部の Cytosolにはエストロジェン•レセプターが存在し,細胞核にはレセプター•エストロジエン複合体が存在にるものとみなされ,この組織に対にるエストロジェンの作用は血液中のエストロジェンが細胞質中のレセプターと結合し,この複合体が細胞核へ移行するという機序によるものと思われる.
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The presence of sodium molybdate during tissue homogenization is known to increase the number of cytosol binding sites for glucocorticoids, progesterone, androgens and oestrogens. We wondered whether a phenomenon similar to this stabilization of steroid receptors would also occur in thyroxine-binding cytosol protein. We found that the presence of sodium molybdate (10 mmol/l) in rat adenohypophyseal cytosol increased its thyroxine-binding capacity by up to 96%. In the case of binding protein cytosol minus molybdate, Ka = 5.5 X 10(9) l.mol-1, whereas for cytosol plus molybdate Ka(1) = 6.0 X 10(9) l.mol-1 and Ka(2) = 3.0 X 10(10) l.mol-1. Cytosol prepared without molybdate did not contain a binding protein class with a higher Ka. The effect is stereo-specific and the LT4 bond is not displaced by DT4.
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ABSTRACT In the past decades many studies reported Endoplasmic Reticulum (ER) resident proteins to localize to the cytosol but the mechanisms by which this occurs and whether these proteins exert cytosolic functions remain unknown. We found that select ER luminal proteins accumulate in the cytosol of glioblastoma cells isolated from mouse and human tumors. In cultured cells ER protein reflux to the cytosol occurs upon proteostasis perturbation. As such we investigated whether refluxed proteins gain new functions in the cytosol thus providing advantage to tumor cells. Using the ER luminal protein AGR2 as a model, we showed that it is refluxed to the cytosol where it binds and inhibits the tumor suppressor p53. We named this phenomenon ER to Cytosol Signaling (ERCYS) as an ER surveillance mechanism conserved in Eukaryotes to relieve the ER from its contents upon stress and to provide selective advantage to tumor cells through gain-of-cytosolic functions.
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ヒト外陰部の皮膚組織を超遠沈法により, cytosol および crude nuclear extract に分離し, その androgen receptor (AR) を methyltrienolone (R 1881) を ligand とした AR assay を用いて測定し, 次の結果を得た.1. 外陰部皮膚組織の cytosol においてはR 1881 receptor に対する progesterone の競合は軽度であり, triamcinolone acetonide 添加による影響はほとんど認められなかった.2. 正常成人男子11例のARの解離定数 (Kd) は cytosol で0.42±0.17nM, nuclear extractで0. 26±0.06nMであった. また, 外性器発育不全を呈する症例のそれは cytosol で0.54±0.21nM (n=9), nuclear extract で0.31±0.18nM (n=7) と正常成人男子と有意の差は認められなかった.3. 正常成人男子11例のARの結合部位数 (Bmax) は cytosol で5.91±1.84fmol/mg-protein, nuclear extract で18.0±5.18fmol/mg-protein であった. 一方, 外性器発育不全を呈する症例では cytosol ではn. d. から高値までの変動が認められたが, nuclear extract では全例低値であった. 特に, 精巣性女性化症完全型の1例では cytosol, nuclear extract ともn. d. であった.以上より, 本測定法は外陰部皮膚組織におけるAR測定の簡便, 迅速な方法であり, 性分化異常症の診断に有用であることが推察された.
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Two cyclic AMP-independent protein kinases(CK 1 and CK 2) in the cytosol fraction of AH-66 hepatoma cells have been purified to homogeneity. CK 1 and CK 2 had molecular weights of 36,000 and 340,000, respectively, as determined by gel filtration. CK 1 consists of a single polypeptide and;CK 2 is composed of three subunits of 43,000, 42,000, and 26,000 molecular weights. CK 1 and the 26,000 molecular weight subunit of CK 2 were autophosphorylated. CK 1 preferentially used ATP as phosphate donor, whereas CK 2 utilized both ATP and GTP. Both enzymes markedly catalyzed the phosphorylation of AH-66 cytosolic proteins with molecular weights of 125,000, 95,000, and 40,000. In order to examine whether these phosphoproteins are specifically present in AH-66 cytosol, CK 1 enzymes purified from AH-66 and liver cytosol were added back to AH-66 and liver cytosol. The CK 1 enzymes from both AH-66 cytosol and liver cytosol markedly catalyzed the phosphorylation of these phosphoproteins in AH-66 cytosol. These phosphoproteins in liver cytosol were less intensely phosphorylated by the addition of the CK 1 enzymes from both sources. From these results we conclude that these phosphoproteins are present in both AH-66 cytosol and liver cytosol,but are highly concentrated in AH-66 cytosol.
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