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Bicc1 Polymerization Regulates the Localization and Silencing of Bound mRNA

Benjamin Rothé1, Lucia Leal-Esteban1, Florian Bernet1

  • 1Ecole Polytechnique Fédérale de Lausanne (EPFL), SV ISREC, Lausanne, Switzerland.

Molecular and Cellular Biology
|July 29, 2015
PubMed

Insights

The RNA-binding protein Bicaudal-C (Bicc1) requires polymerization via its SAM domain to stabilize and silence target mRNAs, preventing cyst formation and Wnt pathway dysregulation.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Genetics

Background:

  • Loss of RNA-binding protein Bicaudal-C (Bicc1) causes renal and pancreatic cysts and Wnt/β-catenin signaling defects.
  • Renal cysts are associated with impaired silencing of Bicc1 target mRNAs, such as adenylate cyclase 6 (AC6).
  • Bicc1's N-terminal KH domains bind RNA, while its C-terminal SAM domain mediates self-polymerization and localization to cytoplasmic foci.

Purpose of the Study:

  • To investigate the role of Bicc1 SAM domain polymerization in mRNA silencing and protein stability.
  • To determine if SAM domain polymerization is essential for Bicc1's function in regulating Wnt/β-catenin signaling.
  • To assess the disease relevance of Bicc1 polymerization defects, particularly in the context of the bpk mutant.

Main Methods:

  • Structure modeling of the Bicc1 SAM domain to predict polymerization interfaces.
  • Site-directed mutagenesis of SAM domain residues predicted to be involved in polymerization.
  • Analysis of Bicc1 localization, mRNA silencing, protein stability, and Wnt/β-catenin pathway activity in wild-type and mutant cells.
  • Phenotypic analysis of bpk mutant Bicc1 C-terminal extension.

Main Results:

  • SAM domain polymerization concentrates Bicc1 in cytoplasmic clusters, which is crucial for specific mRNA localization and silencing.
  • Defective SAM polymerization reduces Bicc1 stability, indirectly decreasing inhibition of Dishevelled 2 in the Wnt/β-catenin pathway.
  • Aberrant C-terminal extension of the SAM domain in bpk mutant Bicc1 recapitulates these silencing and stability defects.

Conclusions:

  • Bicc1 polymerization via its SAM domain is a novel mechanism for stabilizing the protein and creating platforms for mRNA silencing.
  • This polymerization process is critical for preventing renal cysts and maintaining proper Wnt/β-catenin signaling during development.
  • SAM domain polymerization represents a disease-relevant mechanism underlying cystogenesis and developmental signaling defects.

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