An atypical and functionally diverse family of Kunitz-type cysteine/serine proteinase inhibitors secreted by the helminth parasite Fasciola hepatica.

Smith, David ORCID: 0000-0002-5158-0522, Cwiklinski, Krystyna ORCID: 0000-0001-5577-2735, Jewhurst, Heather, Tikhonova, Irina G and Dalton, John P (2020) An atypical and functionally diverse family of Kunitz-type cysteine/serine proteinase inhibitors secreted by the helminth parasite Fasciola hepatica. Scientific reports, 10 (1). 20657-.

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Abstract

Fasciola hepatica is a global parasite of humans and their livestock. Regulation of parasite-secreted cathepsin L-like cysteine proteases associated with virulence is important to fine-tune parasite-host interaction. We uncovered a family of seven Kunitz-type (FhKT) inhibitors dispersed into five phylogenetic groups. The most highly expressed FhKT genes (group FhKT1) are secreted by the newly excysted juveniles (NEJs), the stage responsible for host infection. The FhKT1 inhibitors do not inhibit serine proteases but are potent inhibitors of parasite cathepsins L and host lysosomal cathepsin L, S and K cysteine proteases (inhibition constants < 10 nM). Their unusual inhibitory properties are due to (a) Leu¹⁵ in the reactive site loop P1 position that sits at the water-exposed interface of the S1 and S1' subsites of the cathepsin protease, and (b) Arg¹⁹ which forms cation-π interactions with Trp²⁹¹ of the S1' subsite and electrostatic interactions with Asp¹²⁵ of the S2' subsite. FhKT1.3 is exceptional, however, as it also inhibits the serine protease trypsin due to replacement of the P1 Leu¹⁵ in the reactive loop with Arg¹⁵. The atypical Kunitz-type inhibitor family likely regulate parasite cathepsin L proteases and/or impairs host immune cell activation by blocking lysosomal cathepsin proteases involved in antigen processing and presentation.

Item Type:	Article
Uncontrolled Keywords:	Lysosomes, Animals, Cattle, Humans, Helminths, Fasciola hepatica, Parasites, Cysteine, Cathepsins, Trypsin, Helminth Proteins, Cysteine Proteinase Inhibitors, Serine Proteinase Inhibitors, Phylogeny, Host-Parasite Interactions, Serine Proteases
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	24 Feb 2022 09:31
Last Modified:	14 Mar 2024 17:46
DOI:	10.1038/s41598-020-77687-7
Open Access URL:	https://www.nature.com/articles/s41598-020-77687-7
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3149575