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.
Highlights
The high temperature requirement A (HtrA) family consists of highly conserved, multidomain proteins that are present in all kingdoms of cellular life (Clausen et al, 2002)
We found that high temperature requirement A1 (HtrA1) co-aligned with vimentin intermediate filaments (IFs), and upon endoplasmic reticulum (ER) stress, trafficked to the aggresome at the microtubule organizing center (MTOC)
A previous evolutionary study of Mac25-containing proteins in vertebrates placed the HtrA family in an unrelated clade from the IGFbinding protein (IGFBP), despite the fact that HtrA1, HtrA3, and HtrA4 share the same N-terminal Mac25 and Kazal-type inhibitor (KI) domains (Rodgers et al, 2008). Aside from these existing reports, there is a gap in our understanding of when and how these N-domains were acquired by the HtrA family
Summary
The high temperature requirement A (HtrA) family consists of highly conserved, multidomain proteins that are present in all kingdoms of cellular life (Clausen et al, 2002). Their importance is underscored by the identification of developmental (Hara et al, 2009; Tiaden et al, 2012a) or age-associated (Kooistra et al, 2009) human disorders linked to HtrAs, making this gene family a fertile ground for drug discovery. The structure for full-length human HtrA1 at ∼10 Å resolution places some ambiguity in the relationship between the N-terminal and core domains (Eigenbrot et al, 2012), and the available crystal structures of human HtrA1 truncate the N-domains (Truebestein et al, 2011; Eigenbrot et al, 2012)
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