Intracellular autoactivation of TMPRSS11A, an airway epithelial transmembrane serine protease.
TMPRSS11A
cell surface enzyme
coronavirus
protease
proteolytic enzyme
serine protease
spike protein
transmembrane domain
type II transmembrane serine protease
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
04 09 2020
04 09 2020
Historique:
received:
25
05
2020
revised:
14
07
2020
pubmed:
18
7
2020
medline:
20
9
2020
entrez:
18
7
2020
Statut:
ppublish
Résumé
Type II transmembrane serine proteases (TTSPs) are a group of enzymes participating in diverse biological processes. Some members of the TTSP family are implicated in viral infection. TMPRSS11A is a TTSP expressed on the surface of airway epithelial cells, which has been shown to cleave and activate spike proteins of the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome coronaviruses (CoVs). In this study, we examined the mechanism underlying the activation cleavage of TMPRSS11A that converts the one-chain zymogen to a two-chain enzyme. By expression in human embryonic kidney 293, esophageal EC9706, and lung epithelial A549 and 16HBE cells, Western blotting, and site-directed mutagenesis, we found that the activation cleavage of human TMPRSS11A was mediated by autocatalysis. Moreover, we found that TMPRSS11A activation cleavage occurred before the protein reached the cell surface, as indicated by studies with trypsin digestion to remove cell surface proteins, treatment with cell organelle-disturbing agents to block intracellular protein trafficking, and analysis of a soluble form of TMPRSS11A without the transmembrane domain. We also showed that TMPRSS11A was able to cleave the SARS-CoV-2 spike protein. These results reveal an intracellular autocleavage mechanism in TMPRSS11A zymogen activation, which differs from the extracellular zymogen activation reported in other TTSPs. These findings provide new insights into the diverse mechanisms in regulating TTSP activation.
Identifiants
pubmed: 32675285
pii: S0021-9258(17)49983-2
doi: 10.1074/jbc.RA120.014525
pmc: PMC7476710
doi:
Substances chimiques
Membrane Proteins
0
Spike Glycoprotein, Coronavirus
0
TMPRSS11A protein, human
0
spike protein, SARS-CoV-2
0
Serine Proteases
EC 3.4.-
Trypsin
EC 3.4.21.4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12686-12696Informations de copyright
© 2020 Zhang et al.
Déclaration de conflit d'intérêts
Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.
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