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Ubiquitin-Dependent Modification of Skeletal Muscle by the Parasitic Nematode, Trichinella spiralis

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Title: Ubiquitin-Dependent Modification of Skeletal Muscle by the Parasitic Nematode, Trichinella spiralis
Authors: White, RR
Ponsford, AH
Weekes, MP
Rodrigues, RB
Ascher, DB
Mol, M
Selkirk, ME
Gygi, SP
Sanderson, CM
Artavanis-Tsakonas, K
Item Type: Journal Article
Abstract: Trichinella spiralis is a muscle-specific parasitic worm that is uniquely intracellular. T. spiralis reprograms terminally differentiated skeletal muscle cells causing them to de-differentiate and re-enter the cell cycle, a process that cannot occur naturally in mammalian skeletal muscle cells, but one that holds great therapeutic potential. Although the host ubiquitin pathway is a common target for viruses and bacteria during infection, its role in parasite pathogenesis has been largely overlooked. Here we demonstrate that the secreted proteins of T. spiralis contain E2 Ub-conjugating and E3 Ub-ligase activity. The E2 activity is attributed to TsUBE2L3, a novel and conserved T. spiralis enzyme located in the secretory organ of the parasite during the muscle stages of infection. TsUBE2L3 cannot function with any T.spiralis secreted E3, but specifically binds to a panel of human RING E3 ligases, including the RBR E3 ARIH2 with which it interacts with a higher affinity than the mammalian ortholog UbcH7/ UBE2L3. Expression of TsUBE2L3 in skeletal muscle cells causes a global downregulation in protein ubiquitination, most predominantly affecting motor, sarcomeric and extracellular matrix proteins, thus mediating their stabilization with regards to proteasomal degradation. This effect is not observed in the presence of the mammalian ortholog, suggesting functional divergence in the evolution of the parasite protein. These findings demonstrate the first example of host-parasite interactions via a parasite-derived Ub conjugating enzyme; an E2 that demonstrates a novel muscle protein stabilization function.
Issue Date: 21-Nov-2016
Date of Acceptance: 4-Oct-2016
URI: http://hdl.handle.net/10044/1/49684
DOI: https://dx.doi.org/10.1371/journal.ppat.1005977
ISSN: 1553-7366
Publisher: Public Library of Science
Journal / Book Title: PLoS Pathogens
Volume: 12
Issue: 11
Copyright Statement: © 2016 White et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Microbiology
Parasitology
Virology
IN-VITRO
QUANTITATIVE PROTEOMICS
CONJUGATING ENZYME
MASS-SPECTROMETRY
PROTEIN
LIGASE
CELLS
PROTEASOME
EXPRESSION
LARVAE
Animals
Chromatography, Liquid
HEK293 Cells
Helminth Proteins
Host-Parasite Interactions
Humans
Immunoprecipitation
Muscle, Skeletal
Rats
Rats, Sprague-Dawley
Tandem Mass Spectrometry
Trichinella spiralis
Trichinellosis
Ubiquitin
Ubiquitin-Conjugating Enzymes
Ubiquitination
0605 Microbiology
1107 Immunology
1108 Medical Microbiology
Publication Status: Published
Open Access location: https://doi.org/10.1371/journal.ppat.1005977
Article Number: ARTN e1005977
Appears in Collections:Faculty of Natural Sciences