LRRC15 inhibits SARS-CoV-2 cellular entry in trans.
LRRC15 inhibits SARS-CoV-2 cellular entry in trans.
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DOI：
10.1371/journal.pbio.3001805
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发表时间：
2022-10
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
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严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）感染由进入受体血管紧张素转换酶2（ACE 2）介导。虽然附着因子和辅助受体促进进入广泛研究，细胞进入因子抑制病毒进入很大程度上是未知的。使用表面组CRISPR激活筛选，我们鉴定了人LRRC 15作为SARS-CoV-2进入的抑制性附着因子。LRRC 15以中等亲和力直接结合刺突蛋白的受体结合结构域（RBD）并抑制刺突介导的进入。对人肺单细胞RNA测序数据集的分析揭示，LRRC 15的表达主要在成纤维细胞中检测到，并且在COVID-19患者的病理性成纤维细胞中特别富集。ACE 2和LRRC 15在肺中的相同细胞类型中不共表达。引人注目的是，LRRC 15在ACE 2阴性细胞中的表达阻断了尖峰介导的病毒反式进入ACE 2+细胞，表明LRRC 15在生理环境中的保护作用。因此，LRRC 15代表SARS-CoV-2的抑制性附着因子，其调节病毒以反式进入。SARS-CoV-2感染由进入受体ACE 2介导，但抑制病毒进入的细胞进入因子在很大程度上是未知的。这项研究表明，人LRRC 15蛋白在病理成纤维细胞中表达，直接结合到刺突蛋白的受体结合结构域，并抑制SARS-CoV-2刺突介导的病毒进入邻近细胞。
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is mediated by the entry receptor angiotensin-converting enzyme 2 (ACE2). Although attachment factors and coreceptors facilitating entry are extensively studied, cellular entry factors inhibiting viral entry are largely unknown. Using a surfaceome CRISPR activation screen, we identified human LRRC15 as an inhibitory attachment factor for SARS-CoV-2 entry. LRRC15 directly binds to the receptor-binding domain (RBD) of spike protein with a moderate affinity and inhibits spike-mediated entry. Analysis of human lung single-cell RNA sequencing dataset reveals that expression of LRRC15 is primarily detected in fibroblasts and particularly enriched in pathological fibroblasts in COVID-19 patients. ACE2 and LRRC15 are not coexpressed in the same cell types in the lung. Strikingly, expression of LRRC15 in ACE2-negative cells blocks spike-mediated viral entry in ACE2+ cell in trans, suggesting a protective role of LRRC15 in a physiological context. Therefore, LRRC15 represents an inhibitory attachment factor for SARS-CoV-2 that regulates viral entry in trans. SARS-CoV-2 infection is mediated by the entry receptor ACE2, but cellular entry factors that inhibit viral entry are largely unknown. This study shows that human LRRC15 protein is expressed in pathological fibroblasts, directly binds to the receptor-binding domain of spike protein, and inhibits SARS-CoV-2 spike-mediated viral entry in neighboring cells.
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DOI：
10.1126/science.abd3072
发表时间：
2020-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Daly JL;Simonetti B;Klein K;Chen KE;Williamson MK;Antón-Plágaro C;Shoemark DK;Simón-Gracia L;Bauer M;Hollandi R;Greber UF;Horvath P;Sessions RB;Helenius A;Hiscox JA;Teesalu T;Matthews DA;Davidson AD;Collins BM;Cullen PJ;Yamauchi Y
通讯作者：
Yamauchi Y
影响因子：
64.5
作者：
Clausen, Thomas Mandel;Sandoval, Daniel R.;Esko, Jeffrey D.
通讯作者：
Esko, Jeffrey D.
影响因子：
158.5
作者：
Li, Qun;Guan, Xuhua;Feng, Zijian
通讯作者：
Feng, Zijian
DOI：
10.1126/science.abc4730
发表时间：
2020-09-25
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Gu H;Chen Q;Yang G;He L;Fan H;Deng YQ;Wang Y;Teng Y;Zhao Z;Cui Y;Li Y;Li XF;Li J;Zhang NN;Yang X;Chen S;Guo Y;Zhao G;Wang X;Luo DY;Wang H;Yang X;Li Y;Han G;He Y;Zhou X;Geng S;Sheng X;Jiang S;Sun S;Qin CF;Zhou Y
通讯作者：
Zhou Y
影响因子：
64.8
作者：
Delorey TM;Ziegler CGK;Heimberg G;Normand R;Yang Y;Segerstolpe Å;Abbondanza D;Fleming SJ;Subramanian A;Montoro DT;Jagadeesh KA;Dey KK;Sen P;Slyper M;Pita-Juárez YH;Phillips D;Biermann J;Bloom-Ackermann Z;Barkas N;Ganna A;Gomez J;Melms JC;Katsyv I;Normandin E;Naderi P;Popov YV;Raju SS;Niezen S;Tsai LT;Siddle KJ;Sud M;Tran VM;Vellarikkal SK;Wang Y;Amir-Zilberstein L;Atri DS;Beechem J;Brook OR;Chen J;Divakar P;Dorceus P;Engreitz JM;Essene A;Fitzgerald DM;Fropf R;Gazal S;Gould J;Grzyb J;Harvey T;Hecht J;Hether T;Jané-Valbuena J;Leney-Greene M;Ma H;McCabe C;McLoughlin DE;Miller EM;Muus C;Niemi M;Padera R;Pan L;Pant D;Pe'er C;Pfiffner-Borges J;Pinto CJ;Plaisted J;Reeves J;Ross M;Rudy M;Rueckert EH;Siciliano M;Sturm A;Todres E;Waghray A;Warren S;Zhang S;Zollinger DR;Cosimi L;Gupta RM;Hacohen N;Hibshoosh H;Hide W;Price AL;Rajagopal J;Tata PR;Riedel S;Szabo G;Tickle TL;Ellinor PT;Hung D;Sabeti PC;Novak R;Rogers R;Ingber DE;Jiang ZG;Juric D;Babadi M;Farhi SL;Izar B;Stone JR;Vlachos IS;Solomon IH;Ashenberg O;Porter CBM;Li B;Shalek AK;Villani AC;Rozenblatt-Rosen O;Regev A
通讯作者：
Regev A