The transition zone protein Rpgrip1l regulates proteasomal activity at the primary cilium.
The transition zone protein Rpgrip1l regulates proteasomal activity at the primary cilium.
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DOI：
10.1083/jcb.201408060
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发表时间：
2015-07-06
期刊：
影响因子：
--
通讯作者：
Rüther U
中科院分区：
文献类型：
--
作者：
Gerhardt C;Lier JM;Burmühl S;Struchtrup A;Deutschmann K;Vetter M;Leu T;Reeg S;Grune T;Rüther U
Rpgrip1l通过Psmd2调节基底体蛋白酶体活性，从而控制纤毛信号传导。RPGRIP1L的突变导致严重的人类疾病，称为纤毛病。为了揭示RPGRIP1L的分子功能，我们分析了RPGRIP1L−/−小鼠胚胎，这些胚胎表现出纤毛病表型，最迟在出生前后死亡。在这些胚胎中，纤毛介导的信号被严重干扰。Shh信号的缺陷表明，Rpgrip1l缺陷会导致蛋白质降解和蛋白质加工的损伤。事实上，我们检测到纤毛依赖性蛋白酶体活性在Rpgrip1l缺失的情况下降低。我们发现不同的蛋白酶体成分定位在纤毛上，并确定了Psmd2，一个调节蛋白酶体19S亚基的成分，作为Rpgrip1l的相互作用伙伴。蛋白酶体底物的定量分析表明，Rpgrip1l在基底体内特异性调节蛋白酶体活性。我们的研究表明，Rpgrip1l通过Psmd2调节纤毛蛋白酶体的活性来控制纤毛信号传导。
Rpgrip1l regulates proteasomal activity at the basal body via Psmd2 and thereby controls ciliary signaling. Mutations in RPGRIP1L result in severe human diseases called ciliopathies. To unravel the molecular function of RPGRIP1L, we analyzed Rpgrip1l−/− mouse embryos, which display a ciliopathy phenotype and die, at the latest, around birth. In these embryos, cilia-mediated signaling was severely disturbed. Defects in Shh signaling suggested that the Rpgrip1l deficiency causes an impairment of protein degradation and protein processing. Indeed, we detected a cilia-dependent decreased proteasomal activity in the absence of Rpgrip1l. We found different proteasomal components localized to cilia and identified Psmd2, a component of the regulatory proteasomal 19S subunit, as an interaction partner for Rpgrip1l. Quantifications of proteasomal substrates demonstrated that Rpgrip1l regulates proteasomal activity specifically at the basal body. Our study suggests that Rpgrip1l controls ciliary signaling by regulating the activity of the ciliary proteasome via Psmd2.
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