|Title||Bicc1 polymerization regulates the localization and silencing of bound mRNA.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Rothé, B, Leal-Esteban, L, Bernet, F, Urfer, S, Doerr, N, Weimbs, T, Iwaszkiewicz, J, Constam, DB|
|Journal||Mol Cell Biol|
|Date Published||2015 Jul 27|
Loss of the RNA-binding protein Bicaudal-C (Bicc1) provokes renal and pancreatic cysts as well as ectopic Wnt/β-catenin signaling during visceral left-right patterning. Renal cysts are linked to defective silencing of Bicc1 target mRNAs, including adenylate cyclase 6 (AC6). RNA binding of Bicc1 is mediated by N-terminal KH domains, whereas a C-terminal sterile alpha motif (SAM) self-polymerizes in vitro and localizes Bicc1 in cytoplasmic foci in vivo. To assess a role for multimerization in silencing, we mutated SAM domain residues that we predict by structure modelling to polymerize Bicc1 in a left-handed helix. We show that a SAM-SAM interface concentrates Bicc1 in cytoplasmic clusters to specifically localize and silence bound mRNA. In addition, defective polymerization decreases Bicc1 stability and thus indirectly attenuates inhibition of Dishevelled-2 in the Wnt/β-catenin pathway. Importantly, aberrant C-terminal extension of the SAM domain in bpk mutant Bicc1 phenocopied these defects. We conclude that polymerization is a novel disease-relevant mechanism both to stabilize Bicc1 and to present associated mRNAs in specific silencing platforms.
|Alternate Journal||Mol. Cell. Biol.|