title: Bicc1 Polymerization Regulates the Localization and Silencing of Bound mRNA.
abstract: 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 conducted structure modeling and then mutated the SAM domain residues which in this model were predicted 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.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL), SV ISREC, Lausanne, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rothé
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL), SV ISREC, Lausanne, Switzerland.
authors.forename: Lucia
authors.initials: L
authors.lastname: Leal-Esteban
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL), SV ISREC, Lausanne, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Bernet
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL), SV ISREC, Lausanne, Switzerland.
authors.forename: Séverine
authors.initials: S
authors.lastname: Urfer
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, California, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Doerr
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, California, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weimbs
authors.affiliation: Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Iwaszkiewicz
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL), SV ISREC, Lausanne, Switzerland Daniel.Constam@epfl.ch.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Constam
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D021381:Protein Transport; D034622:RNA Interference; D034443:RNA Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C540667:Bicc1 protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins