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

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John D Hulleman1, William E Balch, Jeffery W Kelly

  • 1Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA. hulleman@scripps.edu

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|August 9, 2012
PubMed

Insights

Targeting cellular secretion pathways partially rescues fibulin-3 mutations causing malattia leventinese. Strategies like PERK activation show promise, but translational attenuation is ineffective for fibulin-5 secretion defects.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Fibulin mutations causing secretion deficiencies are linked to diseases like retinopathies and cutis laxa (CL).
  • The R345W fibulin-3 mutant causes malattia leventinese due to endoplasmic reticulum retention and extracellular misfolding.

Purpose of the Study:

  • To investigate therapeutic strategies for fibulin secretion deficiencies by modulating cellular signaling pathways.
  • To determine if translational attenuation can rescue fibulin secretion defects.

Main Methods:

  • Activation of the PERK arm of the unfolded protein response (UPR).
  • Treatment with arsenite to activate a PERK-independent eIF2α kinase.
  • Assessment of mutant fibulin secretion under varying conditions (e.g., temperature).
  • Analysis of the role of activating transcription factor 4 (ATF4) and protein translation.

Main Results:

  • PERK activation partially rescued R345W fibulin-3 secretion via translational attenuation.
  • Arsenite treatment also enhanced R345W fibulin-3 secretion independently of ATF4 and protein translation.
  • Translational attenuation failed to rescue secretion deficiencies in fibulin-5 mutants.
  • Lowered growth temperature improved secretion of CL-associated fibulin mutants, but not via translational attenuation.
  • Protein translation was essential for wild-type and mutant fibulin-5 secretion.

Conclusions:

  • Cellular signaling pathways and proteostasis network components differentially affect fibulin fate.
  • Targeting specific pathways offers a potential therapeutic approach for fibulin-related diseases.
  • Strategies effective for fibulin-3 may not be applicable to fibulin-5 due to distinct secretion requirements.

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