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Translational attenuation differentially alters the fate of disease-associated fibulin proteins

Academic Article
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Overview

authors

  • Hulleman, J. D.
  • Balch, William E.
  • Kelly, Jeffery

publication date

  • 2012

journal

  • FASEB Journal  Journal

abstract

  • Mutations in fibulin proteins that cause cellular secretion deficiencies are linked to a variety of diseases, ranging from retinopathies to cutis laxa (CL). One secretion-deficient fibulin mutant, R345W fibulin-3, causes the macular dystrophy malattia leventinese by increased endoplasmic reticulum retention and/or extracellular misfolding. Herein, we report that small-molecule activation of the PERK arm of the unfolded protein response partially rescues R345W secretion deficiencies through translational attenuation mediated by eIF2α phosphorylation. Enhanced mutant fibulin-3 secretion can also be achieved by activation of a PERK-independent eIF2α kinase through arsenite treatment and is independent of activating transcription factor 4 signaling and protein translation. However, this translational attenuation strategy was unsuccessful for enhancing the secretion deficiencies of fibulin-5 mutants associated with age-related macular degeneration or CL. While lowered growth temperature enhanced the secretion of mutants associated with CL (C217R and S227P), these effects were not mediated through translational attenuation. In stark contrast to the situation with fibulin-3, protein translation was required for efficient wild-type and mutant fibulin-5 secretion. These data suggest that alteration of specific cellular signaling pathways and proteostasis network components can differentially influence fibulin fate, a hypothesis that could be exploited as a therapy for fibulin-related diseases.

subject areas

  • Activating Transcription Factor 4
  • Eukaryotic Initiation Factor-2
  • Extracellular Matrix Proteins
  • HEK293 Cells
  • Humans
  • Luciferases
  • Mutation
  • Protein Processing, Post-Translational
  • Signal Transduction
  • Tacrolimus
  • Transcription Factors
  • eIF-2 Kinase
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Research

keywords

  • age-related macular degeneration
  • cutis laxa
  • eIF2 alpha
  • malattia leventinese
  • proteostasis
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Identity

PubMed Central ID

  • PMC3475254

International Standard Serial Number (ISSN)

  • 0892-6638

Digital Object Identifier (DOI)

  • 10.1096/fj.11-202861

PubMed ID

  • 22872678
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Additional Document Info

start page

  • 4548

end page

  • 4560

volume

  • 26

issue

  • 11

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