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ER stress-induced aggresome trafficking of HtrA1 protects against proteotoxicity

Journal of Molecular Cell Biology 2017年第6期9卷 516-532页

作者： Maximilian J. Gerhardt Joseph A. Marsh Margaux Morrison Andrius Kazlauskas Arogya Khadka Stephan Rosenkranz Margaret M. DeAngelis Magali Saint-Geniez Sarah Melissa P. Jacobo 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 MRC Human Genetics Unit Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh EH4 2XU UK Department of Ophthalmology and Visual Sciences University of Utah and John A. Moran Eye Center Salt Lake City UT 84132 USA

High temperature requirement A1 （HtrA1） belongs to an ancient protein family that is linked to various human disorders. The pre- cise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrAZ 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 impticated in unfotded protein response. ｜n highly secre- tory cells of the retinal pigmented epithelia, endoplasmic reticulum （ER） stress upregulated HtrA1. HtrA1 co-localized with vimen- tin 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 dis- played reduced efficacy in rescuing cells from proteotoxicity. Our results illuminate the integration of HtrA1 in the toolkit of mam- malian cells against protein misfolding and the implications of defects in HtrA1 in proteostasis.

关键词： ER stress unfolded protein response RPE HtrA1 multi-domain protein evolution proteostasis

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