التفاصيل البيبلوغرافية
| العنوان: |
ACE2 acts as a novel regulator of TMPRSS2-catalyzed proteolytic activation of influenza A virus in airway cells |
| المؤلفون: |
Heindl, Miriam Ruth, Rupp, Anna-Lena, Schwerdtner, Marie, Bestle, Dorothea, Harbig, Anne, De Rocher, Amy, Schmacke, Luna C., Staker, Bart, Steinmetzer, Torsten, Stein, David A., Moulton, Hong M., Böttcher-Friebertshäuser, Eva |
| المساهمون: |
Subbarao, Kanta, Deutsche Forschungsgemeinschaft, State of Hesse LOEWE, HHS | NIH | National Institute of Allergy and Infectious Diseases |
| المصدر: |
Journal of Virology ; volume 98, issue 4 ; ISSN 0022-538X 1098-5514 |
| بيانات النشر: |
American Society for Microbiology |
| سنة النشر: |
2024 |
| الوصف: |
The transmembrane serine protease 2 (TMPRSS2) activates the outer structural proteins of a number of respiratory viruses including influenza A virus (IAV), parainfluenza viruses, and various coronaviruses for membrane fusion. Previous studies showed that TMPRSS2 interacts with the carboxypeptidase angiotensin-converting enzyme 2 (ACE2), a cell surface protein that serves as an entry receptor for some coronaviruses. Here, by using protease activity assays, we determine that ACE2 increases the enzymatic activity of TMPRSS2 in a non-catalytic manner. Furthermore, we demonstrate that ACE2 knockdown inhibits TMPRSS2-mediated cleavage of IAV hemagglutinin (HA) in Calu-3 human airway cells and suppresses virus titers 100- to 1.000-fold. Transient expression of ACE2 in ACE2-deficient cells increased TMPRSS2-mediated HA cleavage and IAV replication. ACE2 knockdown also reduced titers of MERS-CoV and prevented S cleavage by TMPRSS2 in Calu-3 cells. By contrast, proteolytic activation and multicycle replication of IAV with multibasic HA cleavage site typically cleaved by furin were not affected by ACE2 knockdown. Co-immunoprecipitation analysis revealed that ACE2-TMPRSS2 interaction requires the enzymatic activity of TMPRSS2 and the carboxypeptidase domain of ACE2. Together, our data identify ACE2 as a new co-factor or stabilizer of TMPRSS2 activity and as a novel host cell factor involved in proteolytic activation and spread of IAV in human airway cells. Furthermore, our data indicate that ACE2 is involved in the TMPRSS2-catalyzed activation of additional respiratory viruses including MERS-CoV. IMPORTANCE Proteolytic cleavage of viral envelope proteins by host cell proteases is essential for the infectivity of many viruses and relevant proteases provide promising drug targets. The transmembrane serine protease 2 (TMPRSS2) has been identified as a major activating protease of several respiratory viruses, including influenza A virus. TMPRSS2 was previously shown to interact with angiotensin-converting enzyme 2 ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1128/jvi.00102-24 |
| الإتاحة: |
https://doi.org/10.1128/jvi.00102-24Test |
| حقوق: |
https://doi.org/10.1128/ASMCopyrightv2Test ; https://journals.asm.org/non-commercial-tdm-licenseTest |
| رقم الانضمام: |
edsbas.7CCA7F5A |
| قاعدة البيانات: |
BASE |
