Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2.
Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2.
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DOI：
10.1038/s41467-022-35590-x
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发表时间：
2022-12-23
影响因子：
16.6
通讯作者：
Wong, Hoi Leong Xavier
中科院分区：
文献类型：
--
作者：
Guo, Xuanming;Cao, Jianli;Cai, Jian-Piao;Wu, Jiayan;Huang, Jiangang;Asthana, Pallavi;Wong, Sheung Kin Ken;Ye, Zi-Wei;Gurung, Susma;Zhang, Yijing;Wang, Sheng;Wang, Zening;Ge, Xin;Kwan, Hiu Yee;Lyu, Aiping;Chan, Kui Ming;Wong, Nathalie;Huang, Jiandong;Zhou, Zhongjun;Bian, Zhao-Xiang;Yuan, Shuofeng;Wong, Hoi Leong Xavier
严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）已引起全球大流行。血管紧张素转换酶2（ACE 2）是SARS冠状病毒2型的进入受体。ACE 2的全长膜形式（memACE 2）经历胞外域脱落以产生脱落的可溶形式（solACE 2），其通过受体介导的内吞作用介导SARS-CoV-2进入。目前，尚不清楚ACE 2脱落的生理调节如何有助于体内COVID-19的病因学。本研究鉴定了膜型1基质金属蛋白酶（MT 1-MMP）作为solACE 2介导的SARS-CoV-2感染的关键宿主蛋白酶。SARS-CoV-2感染导致人肺上皮中与ACE 2共定位的MT 1-MMP激活增加。在机制上，MT 1-MMP直接在M706-S处切割memACE 2以释放solACE 218 -706，solACE 218 -706结合SARS-CoV-2刺突蛋白（S），从而促进SARS-CoV-2进入细胞。人solACE 218 -706使SARS-CoV-2在非允许细胞和天然不敏感的C57 BL/6小鼠中感染。MT 1-MMP活性的抑制抑制了SARS-CoV-2在人类类器官和老年小鼠中的solACE 2定向进入。solACE 2和循环MT 1-MMP两者在老年小鼠和人的血浆中正相关。我们的研究结果提供了体内证据，证明ACE 2脱落对COVID-19病因的贡献。可溶性血管紧张素转换酶2（sACE 2）在SARS-CoV-2感染中的作用尚不清楚。在这里，作者表明，膜1型基质金属蛋白酶（MT 1-MMP）释放sACE 2，以促进SARS-CoV-2细胞进入体外和体内，MT 1-MMP的上调可能有助于增加对SARS-CoV-2感染的易感性。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung epithelium. Mechanistically, MT1-MMP directly cleaves memACE2 at M706-S to release solACE218-706 that binds to the SARS-CoV-2 spike proteins (S), thus facilitating cell entry of SARS-CoV-2. Human solACE218-706 enables SARS-CoV-2 infection in both non-permissive cells and naturally insusceptible C57BL/6 mice. Inhibition of MT1-MMP activities suppresses solACE2-directed entry of SARS-CoV-2 in human organoids and aged mice. Both solACE2 and circulating MT1-MMP are positively correlated in plasma of aged mice and humans. Our findings provide in vivo evidence demonstrating the contribution of ACE2 shedding to the etiology of COVID-19. The role of soluble angiotensin converting enzyme 2 (sACE2) in SARS-CoV-2 infection is not well understood. Here, authors show that membrane type 1 matrix metalloproteinase (MT1-MMP) releases sACE2 to promote SARS-CoV-2 cell entry in vitro and in vivo, and the upregulation of MT1-MMP may contribute to increased susceptibility to SARS-CoV-2 infection in ageing.
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DOI：
10.1074/jbc.m508381200
发表时间：
2006-02-10
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Huang IC;Bosch BJ;Li F;Li W;Lee KH;Ghiran S;Vasilieva N;Dermody TS;Harrison SC;Dormitzer PR;Farzan M;Rottier PJ;Choe H
通讯作者：
Choe H
影响因子：
5.8
作者：
Benlarbi, Mehdi;Laroche, Genevieve;Fink, Corby;Fu, Kathy;Mulloy, Rory P.;Phan, Alexandra;Ariana, Ardeshir;Stewart, Corina M.;Prevost, Jeremie;Beaudoin-Bussieres, Guillaume;Daniel, Redaet;Bo, Yuxia;El Ferri, Omar;Yockell-Lelievre, Julien;Stanford, William L.;Giguere, Patrick M.;Mubareka, Samira;Finzi, Andres;Dekaban, Gregory A.;Dikeakos, Jimmy D.;Cote, Marceline
通讯作者：
Cote, Marceline
影响因子：
5.4
作者：
Glowacka, Ilona;Bertram, Stephanie;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan
通过 MT1-MMP 介导的 GFRAL 裂解调节体重
影响因子：
20.8
作者：
Chow, Chi Fung Willis;Guo, Xuanming;Wong, Hoi Leong Xavier
通讯作者：
Wong, Hoi Leong Xavier
影响因子：
46.9
作者：
Chua, Robert Lorenz;Lukassen, Soeren;Eils, Roland
通讯作者：
Eils, Roland