The KDM6A-KMT2D-p300 axis regulates susceptibility to diverse coronaviruses by mediating viral receptor expression.
The KDM6A-KMT2D-p300 axis regulates susceptibility to diverse coronaviruses by mediating viral receptor expression.
复制标题
DOI：
10.1371/journal.ppat.1011351
复制
发表时间：
2023-07
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
冠状病毒感染的宿主决定因素的鉴定为发病机制提供了信息，并可能提供新的治疗靶点。在这里，我们证明了组蛋白去甲基化酶KDM 6A促进不同冠状病毒的感染，包括SARS-CoV，SARS-CoV-2，MERS-CoV和小鼠肝炎病毒（MHV）的去甲基化酶活性独立的方式。机制研究表明，KDM 6A通过调节多种冠状病毒受体（包括ACE 2、DPP 4和Ceacam 1）的表达来促进病毒进入。重要的是，KDM 6A的TPR结构域是募集组蛋白甲基转移酶KMT 2D和组蛋白去乙酰化酶p300所必需的。这种KDM 6A-KMT 2D-p300复合物一起定位于ACE 2的近端和远端增强子并调节受体表达。值得注意的是，p300催化活性的小分子抑制消除ACE 2和DPP 4表达，并赋予原代人气道和肠上皮细胞对所有主要SARS-CoV-2变体和MERS-CoV的抗性。这些数据突出了KDM 6A-KMT 2D-p300复合物活性在赋予不同冠状病毒易感性方面的作用，并揭示了对抗当前和新兴冠状病毒的潜在泛冠状病毒治疗靶点。一句话总结：KDM 6A/KMT 2D/EP 300轴促进多种病毒受体的表达，并代表了多种冠状病毒的潜在药物靶标。在过去的二十年里，三种高致病性冠状病毒SARS-CoV、MERS-CoV和SARS-CoV-2已经扩散到人类中。重要的是要确定这些病毒如何引起感染的机制，以增加我们对病毒如何引起疾病的理解，并帮助开发针对当前和未来冠状病毒的新疗法。在这里，我们确定了宿主蛋白KDM 6A，KMT 2D和p300对冠状病毒感染至关重要。KDM 6A、KMT 2D和p300是与癌症和发育综合征有关的重要蛋白质。它们修饰组蛋白，而组蛋白调节特定宿主基因的表达。我们发现KDM 6A-KMT 2D-p300轴启动宿主基因ACE 2和DPP 4的表达，这两个基因分别编码SARS样冠状病毒和MERS-CoV的受体。KDM 6A、KMT 2D和p300作用于冠状病毒受体基因的增强子区域以开启受体表达。p300活性的小分子抑制剂阻断细胞系和原代人气道细胞中的受体表达。这种抑制作用耐受性良好，使细胞对感染具有抵抗力。这突出了针对不同冠状病毒感染的KDM 6A-KMT 2D-p300轴的潜力。
Identification of host determinants of coronavirus infection informs mechanisms of pathogenesis and may provide novel therapeutic targets. Here, we demonstrate that the histone demethylase KDM6A promotes infection of diverse coronaviruses, including SARS-CoV, SARS-CoV-2, MERS-CoV and mouse hepatitis virus (MHV) in a demethylase activity-independent manner. Mechanistic studies reveal that KDM6A promotes viral entry by regulating expression of multiple coronavirus receptors, including ACE2, DPP4 and Ceacam1. Importantly, the TPR domain of KDM6A is required for recruitment of the histone methyltransferase KMT2D and histone deacetylase p300. Together this KDM6A-KMT2D-p300 complex localizes to the proximal and distal enhancers of ACE2 and regulates receptor expression. Notably, small molecule inhibition of p300 catalytic activity abrogates ACE2 and DPP4 expression and confers resistance to all major SARS-CoV-2 variants and MERS-CoV in primary human airway and intestinal epithelial cells. These data highlight the role for KDM6A-KMT2D-p300 complex activities in conferring diverse coronaviruses susceptibility and reveal a potential pan-coronavirus therapeutic target to combat current and emerging coronaviruses. One Sentence Summary: The KDM6A/KMT2D/EP300 axis promotes expression of multiple viral receptors and represents a potential drug target for diverse coronaviruses. Three highly pathogenic coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2 have spilled over into the human population in the last two decades. It is important to determine the mechanisms underlying how these viruses cause infection in order to increase our understanding of how viruses cause disease and to aid in the development of new therapeutics against current and future coronaviruses. Here we identify that the host proteins KDM6A, KMT2D, and p300 are critical for coronavirus infection. KDM6A, KMT2D, and p300 are important proteins implicated in cancer and developmental syndromes. They modify histone proteins, which regulate expression of specific host genes. We show that the KDM6A-KMT2D-p300 axis turns on expression of the host genes ACE2 and DPP4, which encode the receptors for SARS-like coronaviruses and MERS-CoV, respectively. KDM6A, KMT2D, and p300 act on the enhancer regions of the coronavirus receptor genes to turn on receptor expression. Small molecule inhibitors of p300 activity block receptor expression in both cell lines and primary human airway cells. This inhibition is well tolerated and makes the cells resistant to infection. This highlights the potential for targeting the KDM6A-KMT2D-p300 axis for diverse coronavirus infections.
登录
查看更多内容
FXR抑制作用可以通过减少ACE2来防止SARS-COV-2感染。
影响因子：
64.8
作者：
Brevini, Teresa;Maes, Mailis;Webb, Gwilym J.;John, Binu, V;Fuchs, Claudia D.;Buescher, Gustav;Wang, Lu;Griffiths, Chelsea;Brown, Marnie L.;Scott, William E., III;Pereyra-Gerber, Pehuen;Gelson, William T. H.;Brown, Stephanie;Dillon, Scott;Muraro, Daniele;Sharp, Jo;Neary, Megan;Box, Helen;Tatham, Lee;Stewart, James;Curley, Paul;Pertinez, Henry;Forrest, Sally;Mlcochova, Petra;Varankar, Sagar S.;Darvish-Damavandi, Mahnaz;Mulcahy, Victoria L.;Kuc, Rhoda E.;Williams, Thomas L.;Heslop, James A.;Rossetti, Davide;Tysoe, Olivia C.;Galanakis, Vasileios;Vila-Gonzalez, Marta;Crozier, Thomas W. M.;Bargehr, Johannes;Sinha, Sanjay;Upponi, Sara S.;Fear, Corrina;Swift, Lisa;Saeb-Parsy, Kourosh;Davies, Susan E.;Wester, Axel;Hagstrom, Hannes;Melum, Espen;Clements, Darran;Humphreys, Peter;Herriott, Jo;Kijak, Edyta;Cox, Helen;Bramwell, Chloe;Valentijn, Anthony;Illingworth, Christopher J. R.;Dahman, Bassam;Bastaich, Dustin R.;Ferreira, Raphaella D.;Marjot, Thomas;Barnes, Eleanor;Moon, Andrew M.;Barritt, Alfred S.;Gupta, Ravindra K.;Baker, Stephen;Davenport, Anthony P.;Corbett, Gareth;Gorgoulis, Vassilis G.;Buczacki, Simon J. A.;Lee, Joo-Hyeon;Matheson, Nicholas J.;Trauner, Michael;Fisher, Andrew J.;Gibbs, Paul;Butler, Andrew J.;Watson, Christopher J. E.;Mells, George F.;Dougan, Gordon;Owen, Andrew;Lohse, Ansgar W.;Vallier, Ludovic;Sampaziotis, Fotios
通讯作者：
Sampaziotis, Fotios
DOI：
10.1073/pnas.0707292104
发表时间：
2007-11-20
影响因子：
11.1
作者：
Hong, SunHwa;Cho, Young-Wook;Ge, Kai
通讯作者：
Ge, Kai
DOI：
10.1056/nejmoa2109072
发表时间：
2021-10-14
期刊：
The New England journal of medicine
影响因子：
--
作者：
Bergwerk M;Gonen T;Lustig Y;Amit S;Lipsitch M;Cohen C;Mandelboim M;Levin EG;Rubin C;Indenbaum V;Tal I;Zavitan M;Zuckerman N;Bar-Chaim A;Kreiss Y;Regev-Yochay G
通讯作者：
Regev-Yochay G
影响因子：
64.8
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
11.2
作者：
Kim JH;Sharma A;Dhar SS;Lee SH;Gu B;Chan CH;Lin HK;Lee MG
通讯作者：
Lee MG