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Bicc1 Polymerization Regulates the Localization and Silencing of Bound mRNA

机译：Bicc1聚合调节绑定的mRNA的本地化和沉默。

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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.
机译：RNA结合蛋白Bicaudal-C（Bicc1）的丢失会在内脏左右模式期间引起肾脏和胰腺囊肿以及异位Wnt /β-catenin信号传导。肾囊肿与Bicc1目标mRNA（包括腺苷酸环化酶6（AC6））的沉默沉默有关。 Bicc1的RNA结合是由N端KH结构域介导的，而C端无菌α基序（SAM）则在体外自我聚合并在细胞质内将Bicc1定位在体内>。为了评估多聚化在沉默中的作用，我们进行了结构建模，然后突变了SAM结构域残基，该残基在该模型中预计将在左手螺旋中聚合Bicc1。我们表明，SAM-SAM接口将Bicc1集中在细胞质簇中，以专门定位和沉默结合的mRNA。此外，聚合缺陷会降低Bicc1的稳定性，从而间接减弱Wnt /β-catenin途径对Disheveled 2的抑制作用。重要的是， bpk 突变体Bicc1中SAM结构域的C末端异常延伸表型化了这些缺陷。我们得出结论，聚合是一种稳定疾病Bicc1并在特定沉默平台中呈现相关mRNA的新型疾病相关机制。

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