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- Title
Translational attenuation differentially alters the fate of disease-associated fibulin proteins.
- Authors
Hulleman, John D.; Balch, William E.; Kelly, Jeffery W.
- Abstract
Mutations in fibulin proteins that cause cellular secretion deficiencies are linked to a variety of diseases, ranging from retinopathies to curls 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 smallmolecule activation of the PERK arm of the unfolded protein response partially rescues R345W secretion deficiencies through translational attenuation mediated by eIF2α phosphorylarlon. Enhanced mutant fibulin-3 secretion can also be achieved by activation of a PERKindependent 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 hypoth esis that could be exploited as a therapy for fibulinrelated diseases.
- Subjects
FIBULINS; PROTEINS; RETINAL degeneration; DYSTROPHY; TRANSCRIPTION factors
- Publication
FASEB Journal, 2012, Vol 26, Issue 11, p4548
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.11-202861