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J Biol Chem. 2013 Apr 23. [Epub ahead of print]
Cleavage activation of the human-adapted influenza virus subtypes by kallikrein-related peptidases 5 and 12.
Hamilton BS, Whittaker GR.
Source
Cornell University, United States.
Abstract
A critical step in the influenza virus replication cycle is the cleavage activation of the hemagglutinin (HA) precursor. Cleavage activation of the influenza HA enables fusion with the host endosome, allowing for release of the viral genome into the host cell. To date, studies have determined that HA activation is driven by trypsin-like, host cell proteases, as well as yet to be identified bacterial proteases. Although the number of host proteases that can activate HA is growing, there is still uncertainty regarding which secreted proteases are able to support multi-cycle replication of influenza. In this study, we have determined that the kallikrein-related peptidases 5 and 12 are secreted from the human respiratory tract and have the ability to cleave and activate HA from the H1, H2, and H3 subtypes. Each peptidase appears to have a preference for particular influenza subtypes, with kallikrein 5 cleaving the H1 and H3 subtypes most efficiently and kallikrein 12 cleaving the H1 and H2 subtypes most efficiently. Cleavage analysis using HA cleavage site peptide mimics revealed that the amino acids neighboring the cleavage site arginine affect cleavage efficiency. Additionally, the thrombolytic zymogens plasminogen, urokinase, and plasma kallikrein have all been shown to cleave and activate influenza, but are mainly found circulating as inactive precursors. Kallikrein 5 and kallikrein 12 were examined for their ability to activate the thrombolytic zymogens and both resulted in activation of each zymogen, with kallikrein 12 being a more potent activator. Activation of the thrombolytic zymogens may therefore allows for both direct and indirect activation of the HA of human-adapted influenza viruses by kallikrein 5 and 12.
PMID:
23612974
[PubMed - as supplied by publisher]
Free full text
Cleavage activation of the human-adapted influenza virus subtypes by kallikrein-related peptidases 5 and 12.
Hamilton BS, Whittaker GR.
Source
Cornell University, United States.
Abstract
A critical step in the influenza virus replication cycle is the cleavage activation of the hemagglutinin (HA) precursor. Cleavage activation of the influenza HA enables fusion with the host endosome, allowing for release of the viral genome into the host cell. To date, studies have determined that HA activation is driven by trypsin-like, host cell proteases, as well as yet to be identified bacterial proteases. Although the number of host proteases that can activate HA is growing, there is still uncertainty regarding which secreted proteases are able to support multi-cycle replication of influenza. In this study, we have determined that the kallikrein-related peptidases 5 and 12 are secreted from the human respiratory tract and have the ability to cleave and activate HA from the H1, H2, and H3 subtypes. Each peptidase appears to have a preference for particular influenza subtypes, with kallikrein 5 cleaving the H1 and H3 subtypes most efficiently and kallikrein 12 cleaving the H1 and H2 subtypes most efficiently. Cleavage analysis using HA cleavage site peptide mimics revealed that the amino acids neighboring the cleavage site arginine affect cleavage efficiency. Additionally, the thrombolytic zymogens plasminogen, urokinase, and plasma kallikrein have all been shown to cleave and activate influenza, but are mainly found circulating as inactive precursors. Kallikrein 5 and kallikrein 12 were examined for their ability to activate the thrombolytic zymogens and both resulted in activation of each zymogen, with kallikrein 12 being a more potent activator. Activation of the thrombolytic zymogens may therefore allows for both direct and indirect activation of the HA of human-adapted influenza viruses by kallikrein 5 and 12.
PMID:
23612974
[PubMed - as supplied by publisher]
Free full text
