Universität zu Köln

Gerhardt, Maximilian J., Marsh, Joseph A., Morrison, Margaux, Kazlauskas, Andrius, Khadka, Arogya, Rosenkranz, Stephan, DeAngelis, Margaret M., Saint-Geniez, Magali and Jacobo, Sarah Melissa P. (2017). ER stress-induced aggresome trafficking of HtrA1 protects against proteotoxicity. J. Mol. Cell Biol., 9 (6). S. 516 - 533. OXFORD: OXFORD UNIV PRESS. ISSN 1759-4685

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Abstract

High temperature requirement A1 (HtrA1) belongs to an ancient protein family that is linked to various human disorders. The precise role 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 misfolding and the implications of defects in HtrA1 in proteostasis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gerhardt, Maximilian J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Marsh, Joseph A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Morrison, Margaux UNSPECIFIED UNSPECIFIED UNSPECIFIED Kazlauskas, Andrius UNSPECIFIED UNSPECIFIED UNSPECIFIED Khadka, Arogya UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenkranz, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED DeAngelis, Margaret M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Saint-Geniez, Magali UNSPECIFIED UNSPECIFIED UNSPECIFIED Jacobo, Sarah Melissa P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-208320
DOI:	10.1093/jmcb/mjx024
Journal or Publication Title:	J. Mol. Cell Biol.
Volume:	9
Number:	6
Page Range:	S. 516 - 533
Date:	2017
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1759-4685
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SERINE-PROTEASE HTRA1; RETINAL-PIGMENT EPITHELIUM; MACULAR DEGENERATION; ENDOPLASMIC-RETICULUM; CHOROIDAL NEOVASCULARIZATION; TRANSLATIONAL REPRESSION; INCREASED EXPRESSION; OXIDATIVE STRESS; BINDING-PROTEIN; GENE-EXPRESSION Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/20832