Vangl2 interaction plays a role in the proteasomal degradation of Prickle2
Vangl2 interaction plays a role in the proteasomal degradation of Prickle2
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DOI：
10.1038/s41598-019-39642-z
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发表时间：
2019-02-27
影响因子：
4.6
通讯作者：
Kishi, Masashi
中科院分区：
文献类型：
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作者：
Nagaoka, Tadahiro;Furuse, Mikio;Kishi, Masashi
含有PET和LIM结构域的刺突蛋白在果蝇的平面细胞极性(PCP)中起着关键作用。据报道，编码人类皮刺同源基因之一的PRICKLE2基因的突变与人类疾病有关，如癫痫和自闭症谱系障碍。为了开发这些难治性疾病的预防和治疗策略，我们研究了转基因HEK293T细胞中Prickle2蛋白水平的调节。Prickle2水平受到与另一种PCP蛋白梵高样蛋白2(Vangl2)的物理相互作用的负调控。Vangl2介导的Prickle2水平的降低至少部分地被蛋白酶体抑制剂或对Cullin-1 E3泛素连接酶的功能性抑制所缓解。此外，Vangl2的表达增强了Prickle2的多泛素化。这种泛素化被泛素突变体的共表达部分阻断，泛素突变体不能通过其Lys48残基聚合来诱导目标蛋白向蛋白酶体降解。综上所述，这些结果表明Prickle2被Vangl2相互作用以Cullin-1依赖的方式多泛素化，以限制其表达水平。在PCP信号依赖的细胞行为中，这种调节可能在局部和暂时微调刺蛋白水平中发挥作用。
The PET and LIM domain-containing protein, Prickle, plays a key role in planar cell polarity (PCP) in Drosophila. It has been reported that mutations in the PRICKLE2 gene, which encodes one of the human orthologues of Prickle, are associated with human diseases such as epilepsy and autism spectrum disorder. To develop preventive and therapeutic strategies for these intractable diseases, we studied the regulation of Prickle2 protein levels in transfected HEK293T cells. Prickle2 levels were negatively regulated by a physical interaction with another PCP protein, Van Gogh-like 2 (Vangl2). The Vangl2-mediated reduction in Prickle2 levels was, at least in part, relieved by proteasome inhibitors or by functional inhibition of the Cullin-1 E3 ubiquitin ligase. Furthermore, the expression of Vangl2 enhanced the polyubiquitination of Prickle2. This ubiquitination was partially blocked by co-expression of a ubiquitin mutant, which cannot be polymerised through their Lys48 residue to induce target proteins toward proteasomal degradation. Together, these results suggest that Prickle2 is polyubiquitinated by the Vangl2 interaction in a Cullin-1-dependent manner to limit its expression levels. This regulation may play a role in the local and temporal fine-tuning of Prickle protein levels during PCP signal-dependent cellular behaviours.