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Type: Journal article
Title: Lysosomal N-acetyltransferase interacts with ALIX and is detected in extracellular vesicles
Author: Fedele, A.O.
Isenmann, S.
Kamei, M.
Snel, M.F.
Trim, P.J.
Proud, C.G.
Hopwood, J.J.
Citation: BBA: Molecular Cell Research, 2018; 1865(10):1451-1464
Publisher: Elsevier
Issue Date: 2018
ISSN: 0167-4889
Statement of
Anthony O. Fedele, Sandra Isenmann, Makoto Kamei, Marten F. Snel, Paul J. Trim, Christopher G. Proud, John J. Hopwood
Abstract: Heparan acetyl CoA: α-glucosaminide N-acetyltransferase (HGSNAT) is a lysosomal multi-pass transmembrane protein whose deficiency may lead to an accumulation of heparan sulphate and the neurodegenerative lysosomal storage disorder mucopolysaccharidosis (MPS) IIIC. In this study, HGSNAT activity was detected in extracellular vesicles isolated from both human urine and culture medium conditioned with HEK 293T cells. We also demonstrate that HGSNAT co-immunoprecipitates with antibodies to ALIX, which is associated with the endosomal sorting complexes required for transport (ESCRT) proteins, and is implicated in the targeting of proteins to intraluminal vesicles of multivesicular bodies, the origin of exosomes. Furthermore, mutation of a putative LYPXnL-based binding site within HGSNAT for the V-domain of ALIX ablated association of HGSNAT with ALIX, post-translational maturation, and transport through the endo-lysosomal network. Unexpectedly, however, a mutation within the V-domain of ALIX demonstrated enhanced HGSNAT association, perhaps due to the actual involvement of other binding sites in this interaction. Indeed, HGSNAT still co-immunoprecipitates with truncations of ALIX lacking the V-domain. Interestingly, CRISPR/Cas9 mediated knock-down of ALIX did not inhibit HGSNAT trafficking through the endo-lysosomal network, suggesting that there is an alternative pathway for trafficking HGSNAT that does not require ALIX. Nonetheless, the targeting of HGSNAT to extracellular vesicles may provide a mechanism to subsequently transfer this enzyme extracellularly to provide a foundation for a therapy for MPS IIIC patients.
Keywords: Extracellular vesicle; endosomal sorting complexes required for transport (ESCRT); ALIX; lysosome; heparan sulfate; heparan acetyl CoA: α-glucosaminide N-acetyltransferase
Rights: © 2018 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbamcr.2018.07.001
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