Clusterin facilitates in vivo clearance of extracellular misfolded proteins

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dc.contributor.authorWyatt, ARen_AU
dc.contributor.authorYerbury, JJen_AU
dc.contributor.authorBerghofer, PJen_AU
dc.contributor.authorGreguric, Ien_AU
dc.contributor.authorKatsifis, Aen_AU
dc.contributor.authorDobson, CMen_AU
dc.contributor.authorWilson, MRen_AU
dc.date.accessioned2014-11-06T04:56:02Zen_AU
dc.date.available2014-11-06T04:56:02Zen_AU
dc.date.issued2011-12-01en_AU
dc.date.statistics2014-11-06en_AU
dc.description.abstractThe extracellular deposition of misfolded proteins is a characteristic of many debilitating age-related disorders. However, little is known about the specific mechanisms that act to suppress this process in vivo. Clusterin (CLU) is an extracellular chaperone that forms stable and soluble complexes with misfolded client proteins. Here we explore the fate of complexes formed between CLU and misfolded proteins both in vitro and in a living organism. We show that proteins injected into rats are cleared more rapidly from circulation when complexed with CLU as a result of their more efficient localization to the liver and that this clearance is delayed by pre-injection with the scavenger receptor inhibitor fucoidan. The CLU– client complexes were found to bind preferentially, in a fucoidan-inhibitable manner, to human peripheral blood monocytes and isolated rat hepatocytes and in the latter cell type were internalized and targeted to lysosomes for degradation. The data suggest, therefore, that CLU plays a key role in an extracellular proteostasis system that recognizes, keeps soluble, and then rapidly mediates the disposal of misfolded proteins. © 2012, Springer.en_AU
dc.description.sponsorshipA. Wyatt is grateful for an Australian Postgraduate Award and an Australian Institute for Nuclear Science and Engineering (AINSE) Postgraduate Award. This work was supported by a grant from the Australian Research Council (DP0773555). C. M. Dobson acknowledges support from the Wellcome Trust.en_AU
dc.identifier.citationWyatt, A. R., Yerbury J. J., Berghofer P., Greguric, I., Katsifis, A., Dobson, C. M., & Wilson, M. R. (2011). Clusterin facilitates in vivo clearance of extracellular misfolded proteins. Cellular and Molecular Life Sciences, 68(23), 3919-3931. doi:10.1007/s00018-011-0684-8en_AU
dc.identifier.govdoc5299en_AU
dc.identifier.issn1420-682Xen_AU
dc.identifier.issue23en_AU
dc.identifier.journaltitleCellular and Molecular Life Sciencesen_AU
dc.identifier.pagination3919-3931en_AU
dc.identifier.urihttp://dx.doi.org/10.1007/s00018-011-0684-8en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/6019en_AU
dc.identifier.volume68en_AU
dc.language.isoenen_AU
dc.publisherSpringer Basel AGen_AU
dc.subjectProteinsen_AU
dc.subjectClearanceen_AU
dc.subjectReceptorsen_AU
dc.subjectApolipoproteinsen_AU
dc.subjectPlasminogenen_AU
dc.subjectBlooden_AU
dc.subjectPhagocytosisen_AU
dc.titleClusterin facilitates in vivo clearance of extracellular misfolded proteinsen_AU
dc.typeJournal Articleen_AU
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