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 ...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.展开更多
文摘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.
