摘要High temperature requirement A1 (HtrA1) belongs to an ancient protein family that is linked to various human disorders.The precise rote of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrA1 remain elusive.In this study,we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates.We hypothesized that human HtrA1 is implicated in unfolded protein response.In highly secretory cells of the retinal pigmented epithelia,endoplasmic reticulum (ER) stress upregulated HtrA1.HtrA1 co-localized with vimentin intermediate filaments in highly arborized fashion.Upon ER stress,HtrA1 tracked along intermediate filaments,which collapsed and bundled in an aggresome at the microtubule organizing center.Gene silencing of HtrA1 altered the schedule and amplitude of adaptive signaling and concomitantly resulted in apoptosis.Restoration of wild-type HtrA1,but not its protease Inactive mutant,was necessary and sufficient to protect from apoptosis.A variant of HtrA1 that harbored exon 1 substitutions displayed reduced efficacy in rescuing cells from proteotoxicity.Our results illuminate the integration of HtrA1 in the toolkit of mammalian cells against protein misfotding and the implications of defects in HtrA1 in proteostasis.
作者单位Department of Ophthalmology, Harvard Medical School, The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, MA 02114,USA;Department Ⅲ of Internal Medicine, Cologne University Heart Center, Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany[1]MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK[2]Department of Ophthalmology and Visual Sciences, University of Utah and John A.Moran Eye Center, Salt Lake City, UT 84132, USA[3]Department of Ophthalmology, Harvard Medical School, The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, MA 02114,USA[4]Department Ⅲ of Internal Medicine, Cologne University Heart Center, Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany[5]
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