1. A secreted BPTI/Kunitz inhibitor domain-containing protein of barber's pole worm interacts with host NLRP3 inflammasome activation-associated G protein subunit to inhibit IL-1β and IL-18 maturation in vitro.
- Author
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Wu F, Wu J, Chen X, Zhou J, Du Z, Tong D, Zhang H, Huang Y, Yang Y, Du A, and Ma G
- Subjects
- Animals, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Sheep, Humans, Host-Parasite Interactions, Interleukin-1beta metabolism, Interleukin-1beta genetics, Helminth Proteins genetics, Helminth Proteins metabolism, Helminth Proteins chemistry, Haemonchus genetics, Inflammasomes metabolism, Inflammasomes genetics, Interleukin-18 metabolism, Interleukin-18 genetics
- Abstract
Protease inhibitors are major components of excretory/secretory products released by parasitic nematodes and have been proposed to play roles in host-parasite interactions. Haemonchus contortus (the barber's pole worm) encodes for several serine protease inhibitors, and in a previous study we identified a trypsin inhibitor-like serine protease inhibitor of this blood-feeding nematode, SPI-I8, as necessary for anticoagulation. Here, we demonstrated that a bovine pancreatic trypsin inhibitor/Kunitz-type serine protease inhibitor (BPTI/Kunitz) domain-containing protein highly expressed in parasitic stages, HCON_00133150, is involved in suppressing proinflammatory cytokine production in mammalian cells. Fluorescent labelling of HCON_00133150 revealed a punctate localisation at the inner hypodermal membrane of H. contortus, an organ closely related to the excretory column. Yeast two-hybrid screening and immunoprecipitation-mass spectrometry identified that the recombinant HCON_00133150 physically interacted with a range of host proteins including the G protein subunit beta 1 of sheep (Ovis aries; OaGNB1), a negative regulator of NLRP3 inflammasome activation. Interestingly, heterologous expression of HCON_00133150 enhanced the inhibitory effect of OaGNB1 on NLRP3 inflammasome and the maturation of proinflammatory cytokines IL-1β and IL-18 in transfected cells. 1-to-1 orthologues (n = 33) of BPTI/Kunitz inhibitor domain-containing proteins were predicted in clades III, IV and V (but not clade I) parasitic nematodes. Structural (tandem BPTI/Kunitz inhibitor domains inverted into the globular reticulation) and functional (a GNB1 enhancer) characterisation of HCON_00133150 and its orthologues elucidated that these molecules might contribute to immune suppression by parasitic nematodes in animals and humans., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interests exist., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
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