Direct role of Bardet-Biedl syndrome proteins in transcriptional regulation
Direct role of Bardet-Biedl syndrome proteins in transcriptional regulation
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DOI：
10.1242/jcs.089375
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发表时间：
2012-01-15
影响因子：
4
通讯作者：
Badano, Jose L.
中科院分区：
文献类型：
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作者：
Gascue, Cecilia;Tan, Perciliz L.;Badano, Jose L.
初级纤毛是保守的细胞器，作为机械和化学传感器以及转导信号级联起着至关重要的作用。因此，纤毛功能障碍导致广泛的表型：纤毛病。Bardet Biedl综合征（BBS）是一种典型的纤毛病，由16个已知基因突变引起。然而，BBS蛋白的生物化学功能尚未完全了解。在这里，我们表明，BBS7蛋白（位于中心体，基体和纤毛）可能有一个核的作用，凭借生物学证实的核出口信号的存在。与这一观察结果一致，我们表明，BBS7与polycomb组（PcG）成员RNF2物理相互作用，并调节其蛋白水平，可能是通过蛋白酶体介导的机制。此外，我们的数据支持其他BBS蛋白的类似作用。重要的是，与该PcG成员的相互作用是生物学相关的，因为BBS蛋白的丢失导致体内内源性RNF2靶点的异常表达，包括对发育以及细胞和组织稳态至关重要的几个基因。我们的数据表明，BBS蛋白在转录调节中具有迄今为止未被认识到的直接作用，并可能扩大支撑患者睫状体表型发育的机制谱。
Primary cilia are conserved organelles that play crucial roles as mechano- and chemosensors, as well as transducing signaling cascades. Consequently, ciliary dysfunction results in a broad range of phenotypes: the ciliopathies. Bardet Biedl syndrome (BBS), a model ciliopathy, is caused by mutations in 16 known genes. However, the biochemical functions of the BBS proteins are not fully understood. Here we show that the BBS7 protein (localized in the centrosomes, basal bodies and cilia) probably has a nuclear role by virtue of the presence of a biologically confirmed nuclear export signal. Consistent with this observation, we show that BBS7 interacts physically with the polycomb group (PcG) member RNF2 and regulate its protein levels, probably through a proteasome-mediated mechanism. In addition, our data supports a similar role for other BBS proteins. Importantly, the interaction with this PcG member is biologically relevant because loss of BBS proteins leads to the aberrant expression of endogenous RNF2 targets in vivo, including several genes that are crucial for development and for cellular and tissue homeostasis. Our data indicate a hitherto unappreciated, direct role for the BBS proteins in transcriptional regulation and potentially expand the mechanistic spectrum that underpins the development of ciliary phenotypes in patients.