The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome.
The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome.
复制标题
DOI：
10.1371/journal.pgen.1004083
复制
发表时间：
2014-02
期刊：
影响因子：
4.5
通讯作者：
Sheffield VC
中科院分区：
文献类型：
--
作者：
Chamling X;Seo S;Searby CC;Kim G;Slusarski DC;Sheffield VC
Bardet-Biedl syndrome (BBS) is a well-known ciliopathy with mutations reported in 18 different genes. Most of the protein products of the BBS genes localize at or near the primary cilium and the centrosome. Near the centrosome, BBS proteins interact with centriolar satellite proteins, and the BBSome (a complex of seven BBS proteins) is believed to play a role in transporting ciliary membrane proteins. However, the precise mechanism by which BBSome ciliary trafficking activity is regulated is not fully understood. Here, we show that a centriolar satellite protein, AZI1 (also known as CEP131), interacts with the BBSome and regulates BBSome ciliary trafficking activity. Furthermore, we show that AZI1 interacts with the BBSome through BBS4. AZI1 is not involved in BBSome assembly, but accumulation of the BBSome in cilia is enhanced upon AZI1 depletion. Under conditions in which the BBSome does not normally enter cilia, such as in BBS3 or BBS5 depleted cells, knock down of AZI1 with siRNA restores BBSome trafficking to cilia. Finally, we show that azi1 knockdown in zebrafish embryos results in typical BBS phenotypes including Kupffer's vesicle abnormalities and melanosome transport delay. These findings associate AZI1 with the BBS pathway. Our findings provide further insight into the regulation of BBSome ciliary trafficking and identify AZI1 as a novel BBS candidate gene. Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive ciliopathy with 18 causative genes reported to date. The syndrome is characterized by obesity, polydactyly, renal defects, hypogenitalism and retinal degeneration. Previous work has illustrated a role for BBS proteins in the trafficking of ciliary cargo proteins including MCHR1, SSTR3, and dopamine receptor 1. In addition, interaction of BBS proteins with other centriolar satellite proteins has been reported. In order to identify novel BBS interacting proteins and novel BBS candidate genes we generated a transgenic BBS4 mouse. In this study, we utilized the transgenic mice to identify a novel BBSome (a complex of eight BBS proteins) interacting protein, AZI1. We show that AZI1 physically binds to the BBSome via BBS4. We also suggest a negative role of AZI1 in ciliary trafficking of the BBSome: when AZI1 is depleted, more BBSome localizes to cilia. Using zebrafish as a model, we show that azi1 morphants are similar to bbs morphants, a finding that further implicates AZI1 with the BBS pathway. Our findings provide further insight into the regulation of BBSome ciliary trafficking and identify AZI1 as a BBS candidate gene.
登录
查看更多内容
影响因子：
3.5
作者：
Pretorius PR;Aldahmesh MA;Alkuraya FS;Sheffield VC;Slusarski DC
通讯作者：
Slusarski DC
影响因子：
4
作者：
Marion, Vincent;Stutzmann, Fanny;Dollfus, Helene
通讯作者：
Dollfus, Helene
影响因子：
--
作者：
Akimov, Vyacheslav;Rigbolt, Kristoffer T. G.;Blagoev, Blagoy
通讯作者：
Blagoev, Blagoy
影响因子：
21.3
作者：
Chih, Ben;Liu, Peter;Peterson, Andrew S.
通讯作者：
Peterson, Andrew S.
影响因子：
3.5
作者：
Baye LM;Patrinostro X;Swaminathan S;Beck JS;Zhang Y;Stone EM;Sheffield VC;Slusarski DC
通讯作者：
Slusarski DC