A helminth cathelicidin-like protein suppresses antigen processing and presentation in macrophages via inhibition of lysosomal vATPase

Robinson, MW; Alvarado, R; To, J; Hutchinson, AT; Dowdell, SN; Lund, M; Turnbull, L; Whitchurch, CB; O'Brien, BA; Dalton, JP; Donnelly, S

A helminth cathelicidin-like protein suppresses antigen processing and presentation in macrophages via inhibition of lysosomal vATPase

Robinson, MW

Alvarado, R

To, J

Hutchinson, AT Dowdell, SN Lund, M

Turnbull, L

Whitchurch, CB

O'Brien, BA

Dalton, JP Donnelly, S

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Publication Type:: Journal Article
Citation:: FASEB Journal, 2012, 26 (11), pp. 4614 - 4627
Issue Date:: 2012-11-01

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Field	Value	Language
dc.contributor.author	Robinson, MW https://orcid.org/0000-0001-7191-0034	en_US
dc.contributor.author	Alvarado, R https://orcid.org/0000-0001-7250-2200	en_US
dc.contributor.author	To, J https://orcid.org/0000-0003-3482-4369	en_US
dc.contributor.author	Hutchinson, AT	en_US
dc.contributor.author	Dowdell, SN	en_US
dc.contributor.author	Lund, M https://orcid.org/0000-0001-7360-5041	en_US
dc.contributor.author	Turnbull, L https://orcid.org/0000-0002-9255-9033	en_US
dc.contributor.author	Whitchurch, CB https://orcid.org/0000-0003-2296-3791	en_US
dc.contributor.author	O'Brien, BA https://orcid.org/0000-0001-5887-2424	en_US
dc.contributor.author	Dalton, JP	en_US
dc.contributor.author	Donnelly, S https://orcid.org/0000-0003-2005-3698	en_US
dc.date.issued	2012-11-01	en_US
dc.identifier.citation	FASEB Journal, 2012, 26 (11), pp. 4614 - 4627	en_US
dc.identifier.uri	http://hdl.handle.net/10453/22179
dc.description.abstract	We previously reported the identification of a novel family of immunomodulatory proteins, termed helminth defense molecules (HDMs), that are secreted by medically important trematode parasites. Since HDMs share biochemical, structural, and functional characteristics with mammalian cathelicidin-like host defense peptides (HDPs), we proposed that HDMs modulate the immune response via molecular mimicry of host molecules. In the present study, we report the mechanism by which HDMs influence the function of macrophages. We show that the HDM secreted by Fasciola hepatica (FhHDM-1) binds to macrophage plasma membrane lipid rafts via selective interaction with phospholipids and/or cholesterol before being internalized by endocytosis. Following internalization, FhHDM-1 is rapidly processed by lysosomal cathepsin L to release a short C-terminal peptide (containing a conserved amphipathic helix that is a key to HDM function), which then prevents the acidification of the endolysosomal compartments by inhibiting vacuolar ATPase activity. The resulting endolysosomal alkalization impedes macrophage antigen processing and prevents the transport of peptides to the cell surface in conjunction with MHC class II for presentation to CD4+ T cells. Thus, we have elucidated a novel mechanism by which helminth pathogens alter innate immune cell function to assist their survival in the host.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/1010197
dc.relation	http://purl.org/au-research/grants/nhmrc/513111
dc.relation.ispartof	FASEB Journal	en_US
dc.relation.isbasedon	10.1096/fj.12-213876	en_US
dc.subject.classification	Biochemistry & Molecular Biology	en_US
dc.subject.mesh	Membrane Microdomains	en_US
dc.subject.mesh	Macrophages	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Fasciola hepatica	en_US
dc.subject.mesh	Helminth Proteins	en_US
dc.subject.mesh	Recombinant Proteins	en_US
dc.subject.mesh	Antigens, Helminth	en_US
dc.subject.mesh	Genes, MHC Class II	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Amino Acid Sequence	en_US
dc.subject.mesh	Protein Binding	en_US
dc.subject.mesh	Molecular Sequence Data	en_US
dc.subject.mesh	Adenosine Triphosphatases	en_US
dc.subject.mesh	Cathepsin L	en_US
dc.title	A helminth cathelicidin-like protein suppresses antigen processing and presentation in macrophages via inhibition of lysosomal vATPase	en_US
dc.type	Journal Article
utslib.citation.volume	11	en_US
utslib.citation.volume	26	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	0606 Physiology	en_US
utslib.for	1116 Medical Physiology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	closed_access
pubs.issue	11	en_US
pubs.publication-status	Published	en_US
pubs.volume	26	en_US

Abstract:

We previously reported the identification of a novel family of immunomodulatory proteins, termed helminth defense molecules (HDMs), that are secreted by medically important trematode parasites. Since HDMs share biochemical, structural, and functional characteristics with mammalian cathelicidin-like host defense peptides (HDPs), we proposed that HDMs modulate the immune response via molecular mimicry of host molecules. In the present study, we report the mechanism by which HDMs influence the function of macrophages. We show that the HDM secreted by Fasciola hepatica (FhHDM-1) binds to macrophage plasma membrane lipid rafts via selective interaction with phospholipids and/or cholesterol before being internalized by endocytosis. Following internalization, FhHDM-1 is rapidly processed by lysosomal cathepsin L to release a short C-terminal peptide (containing a conserved amphipathic helix that is a key to HDM function), which then prevents the acidification of the endolysosomal compartments by inhibiting vacuolar ATPase activity. The resulting endolysosomal alkalization impedes macrophage antigen processing and prevents the transport of peptides to the cell surface in conjunction with MHC class II for presentation to CD4+ T cells. Thus, we have elucidated a novel mechanism by which helminth pathogens alter innate immune cell function to assist their survival in the host.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/22179