DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner.
DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner.
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DOI：
10.1371/journal.pbio.3002097
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发表时间：
2023-06
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
识别严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的宿主基因有可能揭示新的药物靶点，并进一步加深我们对冠状病毒疾病2019(新冠肺炎)的理解。我们之前进行了全基因组CRISPR/Cas9筛查，以确定高致病性人类冠状病毒的前宿主因子。跨多种细胞类型的不同冠状病毒几乎不需要宿主因子，但DYRK1A是这样的一个例外。虽然DYRK1A在冠状病毒感染中的作用以前没有被描述，但它编码双特异性酪氨酸磷酸化调节的Kase1A，并且已知调节细胞的增殖和神经元的发育。在这里，我们证明了DYRK1A调控ACE2和DPP4的转录不依赖于其催化激酶功能，以支持SARS-CoV、SARS-CoV-2和中东呼吸综合征冠状病毒(MERS-CoV)的进入。我们发现DYRK1A促进了ACE2启动子和可能的远端增强子的DNA可及性，促进了转录和基因表达。最后，我们使用非人类灵长类和人类起源的细胞验证了DYRK1A的前病毒活性在物种之间是保守的。综上所述，我们报道了DYRK1A是一种新的ACE2和DPP4表达调节因子，可能决定了其对多种高致病性人类冠状病毒的易感性。本研究发现，双特异性酪氨酸磷酸化调节激酶1A(DYRK1A)可以通过驱动冠状病毒受体基因座染色质的可及性和主动转录来促进冠状病毒的进入，而不依赖于其催化功能。
Identifying host genes essential for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has the potential to reveal novel drug targets and further our understanding of Coronavirus Disease 2019 (COVID-19). We previously performed a genome-wide CRISPR/Cas9 screen to identify proviral host factors for highly pathogenic human coronaviruses. Few host factors were required by diverse coronaviruses across multiple cell types, but DYRK1A was one such exception. Although its role in coronavirus infection was previously undescribed, DYRK1A encodes Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A and is known to regulate cell proliferation and neuronal development. Here, we demonstrate that DYRK1A regulates ACE2 and DPP4 transcription independent of its catalytic kinase function to support SARS-CoV, SARS-CoV-2, and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) entry. We show that DYRK1A promotes DNA accessibility at the ACE2 promoter and a putative distal enhancer, facilitating transcription and gene expression. Finally, we validate that the proviral activity of DYRK1A is conserved across species using cells of nonhuman primate and human origin. In summary, we report that DYRK1A is a novel regulator of ACE2 and DPP4 expression that may dictate susceptibility to multiple highly pathogenic human coronaviruses. This study reveals that Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A (DYRK1A) can facilitate coronavirus entry by driving chromatin accessibility and active transcription at coronavirus receptor gene loci, independent of its catalytic function.
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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
影响因子：
64.5
作者：
Daniloski Z;Jordan TX;Wessels HH;Hoagland DA;Kasela S;Legut M;Maniatis S;Mimitou EP;Lu L;Geller E;Danziger O;Rosenberg BR;Phatnani H;Smibert P;Lappalainen T;tenOever BR;Sanjana NE
通讯作者：
Sanjana NE
影响因子：
5.4
作者：
Cohen, M. J.;Yousef, A. F.;Mymryk, J. S.
通讯作者：
Mymryk, J. S.
影响因子：
16
作者：
Di Vona, Chiara;Bezdan, Daniela;de la Luna, Susana
通讯作者：
de la Luna, Susana
影响因子：
30.8
作者：
Biering, Scott B.;Sarnik, Sylvia A.;Wang, Eleanor;Zengel, James R.;Leist, Sarah R.;Schafer, Alexandra;Sathyan, Varun;Hawkins, Padraig;Okuda, Kenichi;Tau, Cyrus;Jangid, Aditya R.;Duffy, Connor, V;Wei, Jin;Gilmore, Rodney C.;Alfajaro, Mia Madel;Strine, Madison S.;Nguyenla, Xammy;Van Dis, Erik;Catamura, Carmelle;Yamashiro, Livia H.;Belk, Julia A.;Begeman, Adam;Stark, Jessica C.;Shon, D. Judy;Fox, Douglas M.;Ezzatpour, Shahrzad;Huang, Emily;Olegario, Nico;Rustagi, Arjun;Volmer, Allison S.;Livraghi-Butrico, Alessandra;Wehri, Eddie;Behringer, Richard R.;Cheon, Dong-Joo;Schaletzky, Julia;Aguilar, Hector C.;Puschnik, Andreas S.;Button, Brian;Pinsky, Benjamin A.;Blish, Catherine A.;Baric, Ralph S.;O'Neal, Wanda K.;Bertozzi, Carolyn R.;Wilen, Craig B.;Boucher, Richard C.;Carette, Jan E.;Stanley, Sarah A.;Harris, Eva;Konermann, Silvana;Hsu, Patrick D.
通讯作者：
Hsu, Patrick D.