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

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.

• Authors: John D Hulleman, William E Balch, Jeffery W Kelly
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 26 Issue 11 Pg. 4548-60 (Nov 2012) ISSN: 1530-6860 [Electronic] United States
• PMID: 22872678 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AP20187
• ATF4 protein, human
• EFEMP1 protein, human
• Eukaryotic Initiation Factor-2
• Extracellular Matrix Proteins
• FBLN5 protein, human
• Transcription Factors
• Activating Transcription Factor 4
• Luciferases
• PERK kinase
• eIF-2 Kinase
• Tacrolimus

Topics

• Activating Transcription Factor 4
• Eukaryotic Initiation Factor-2 (genetics, metabolism)
• Extracellular Matrix Proteins (genetics, metabolism)
• HEK293 Cells
• Humans
• Luciferases
• Mutation
• Protein Processing, Post-Translational (physiology)
• Signal Transduction
• Tacrolimus (analogs & derivatives)
• Transcription Factors
• eIF-2 Kinase (genetics, metabolism)