Ubiquitylation of BBSome is required for ciliary assembly and signaling.
Ubiquitylation of BBSome is required for ciliary assembly and signaling.
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DOI：
10.15252/embr.202255571
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发表时间：
2023-04-05
期刊：
影响因子：
7.7
通讯作者：
Feliciello, Antonio
中科院分区：
文献类型：
--
作者：
Chiuso, Francesco;delle Donne, Rossella;Giamundo, Giuliana;Rinaldi, Laura;Borzacchiello, Domenica;Moraca, Federica;Intartaglia, Daniela;Iannucci, Rosa;Senatore, Emanuela;Lignitto, Luca;Garbi, Corrado;Conflitti, Paolo;Catalanotti, Bruno;Conte, Ivan;Feliciello, Antonio
Bardet - Biedl综合征（BBS）是一种以视网膜变性、肥胖、肾脏异常、轴后多指畸形和发育缺陷为特征的纤毛病。BBS中突变的基因编码BBSome的成分和调节因子，BBSome是一种控制初级纤毛内货物和受体运输的八聚体复合体。尽管BBSome的结构和功能已被广泛研究，但泛素信号传导对BBSome的影响在很大程度上是未知的。我们发现E3泛素连接酶PJA2是纤毛室的新居民和BBSome的调节剂。在GPCR - cAMP刺激下，PJA2泛素化BBSome亚基。研究表明，赖氨酸143位点BBS1的泛素化增加了BBSome的稳定性，并促进其与BBS3的结合，BBS3是一种类似Arf的GTPase蛋白，控制BBSome对纤毛膜的靶向。PJA2的下调或泛素化缺陷BBS1突变体（BBS1K143R）的表达会影响G蛋白偶联受体（gpcr）的转运和Shh依赖基因的转录。体内BBS1K143R的表达损害纤毛的形成、胚胎发育和光感受器的形态发生，从而再现了medaka鱼模型中的BBS表型。PJA2是睫状体间室的一种新居民。在GPCR - cAMP刺激下，PJA2泛素化BBSome亚基，并控制BBSome在纤毛上的组装和拆卸。泛素化缺陷可能导致medaka鱼Bardet - Biedl综合征。
Bardet‐Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, renal abnormalities, postaxial polydactyly, and developmental defects. Genes mutated in BBS encode for components and regulators of the BBSome, an octameric complex that controls the trafficking of cargos and receptors within the primary cilium. Although both structure and function of the BBSome have been extensively studied, the impact of ubiquitin signaling on BBSome is largely unknown. We identify the E3 ubiquitin ligase PJA2 as a novel resident of the ciliary compartment and regulator of the BBSome. Upon GPCR‐cAMP stimulation, PJA2 ubiquitylates BBSome subunits. We demonstrate that ubiquitylation of BBS1 at lysine 143 increases the stability of the BBSome and promotes its binding to BBS3, an Arf‐like GTPase protein controlling the targeting of the BBSome to the ciliary membrane. Downregulation of PJA2 or expression of a ubiquitylation‐defective BBS1 mutant (BBS1K143R) affects the trafficking of G‐protein‐coupled receptors (GPCRs) and Shh‐dependent gene transcription. Expression of BBS1K143R in vivo impairs cilium formation, embryonic development, and photoreceptors' morphogenesis, thus recapitulating the BBS phenotype in the medaka fish model. PJA2 is a novel resident of the ciliary compartment. Upon GPCR‐cAMP stimulation, PJA2 ubiquitylates BBSome subunits and controls the assembly and disassembly of BBSome at cilia. Defects in ubiquitylation may induce Bardet‐Biedl syndrome in medaka fish.
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影响因子：
2.9
作者：
Jacobson, MP;Pincus, DL;Friesner, RA
通讯作者：
Friesner, RA
DOI：
10.1073/pnas.0914785107
发表时间：
2010-08-31
影响因子：
11.1
作者：
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通讯作者：
Banfi, Sandro
影响因子：
6.3
作者：
de Jong, Djurre H.;Baoukina, Svetlana;Marrink, Siewert J.
通讯作者：
Marrink, Siewert J.
影响因子：
4.6
作者：
Conte, Ivan;Marco-Ferreres, Raquel;Bovolenta, Paola
通讯作者：
Bovolenta, Paola
影响因子：
16.8
作者：
Akimov, Vyacheslav;Barrio-Hernandez, Inigo;Blagoev, Blagoy
通讯作者：
Blagoev, Blagoy