Cleavage Activation of the Human-Adapted Influenza Virus Subtypes by Matriptase Reveals both Subtype and Strain Specificities

Abstract

Cleavage activation of the hemagglutinin (HA) precursor is an essential step in the influenza virus replication cycle that is driven by host cell proteases. HA cleavage activation is required for virus-endosome membrane fusion and the subsequent release of the influenza virus genome into the cytoplasm. Previous studies have determined that HA cleavage is most likely driven by either membrane-bound or extracellular trypsin-like proteases that reside in the respiratory tract. However, there is still uncertainty regarding which proteases are critical for HA cleavage in vivo. Therefore, further investigation of HA cleavage activation is needed in order to gain insight into the critical proteases involved. Matriptase is a member of the type II transmembrane serine protease family that is highly expressed in a membrane-bound form throughout the respiratory tract. One feature of matriptase is that, once activated, the catalytic domain is secreted into the extracellular space and so serves as a functional extracellular protease. In this study, we have determined that the secreted, catalytic domain of matriptase has the ability to cleave and activate HA from the influenza virus H1 subtype but not the H2 and H3 subtypes. Furthermore, matriptase selectively cleaved the HA of particular strains within the H1 subtype, revealing both subtype and H1 strain specificity. Matriptase was also found to activate thrombolytic zymogens that have been shown to cleave and activate the influenza virus HA. Our data demonstrate that matriptase has the ability to cleave HA directly or indirectly by activating HA-cleaving zymogens.

Matriptase, HAT, and TMPRSS2 Activate the Hemagglutinin of H9N2 Influenza A Viruses

“…The cleavage site of HA0 is located in a prominent surface loop (59), and the conformation and exposure of the loop or the presence of carbohydrate side chains may interfere with access of different proteases to different HA subtypes. During preparation of this article, a study by Hamilton et al was published that investigated activation of HA of human influenza viruses of subtypes H1 and H3 by recombinant soluble matriptase (60). In agreement with our results, the HA of H1-SC18 and the HA of a 1968 H3N2 pandemic isolate were not cleaved by matriptase.…”

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

“…Among the suggested human candidates are the kallikreins KLK-5 and KLK-12 [61] or the type II membrane-bound serine proteases HAT (human airway trypsin-like protease or TMPRSS11D) [62], TMPRSS4 [63], DESC1, and MSPL (TMPRSS13) [64]. Despite controversy results, a few H1 subtypes might be also activated by matriptase in addition to TMPRSS2 [65,66]. The contribution of these proteases to HA cleavage in human airways, however, remains to be investigated.…”

Changing the selectivity profile – from substrate analog inhibitors of thrombin and factor Xa to potent matriptase inhibitors

“…Moreover, a strong increase in matriptase expression was observed in inflammatory skin disorders 16 . Recent findings suggest that the host protease matriptase might also be involved in the activation of certain H1 and H9 influenza virus hemagglutinins, which is essential for virus propagation 17,18 . Therefore, matriptase emerged as a potential drug target, especially for the treatment of epithelial tumors.…”