Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Montevideo, CP 11400, Uruguay.
J Cell Sci. 2012 Jan 15;125(Pt 2):362-75. doi: 10.1242/jcs.089375. Epub 2012 Feb 2.
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.
原发性纤毛是保守的细胞器，作为机械感受器和化学感受器，以及信号转导级联的转导，发挥着至关重要的作用。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 个已知基因的突变引起。然而，BBS 蛋白的生化功能尚不完全清楚。在这里，我们表明 BBS7 蛋白（定位于中心体、基底体和纤毛中）可能具有核作用，因为存在生物学上确认的核输出信号。与这一观察结果一致，我们表明 BBS7 与多梳组（PcG）成员 RNF2 相互作用，并通过蛋白酶体介导的机制调节其蛋白质水平，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 成员的相互作用具有生物学意义，因为 BBS 蛋白的缺失导致内源性 RNF2 靶基因在体内的异常表达，包括几个对发育以及细胞和组织稳态至关重要的基因。我们的数据表明，BBS 蛋白在转录调控中具有迄今未被认识的直接作用，并可能扩展了支持患者纤毛病发生的机制范围。
