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纤毛病复合物位于过渡区，作为一个特权膜结构域保护纤毛。

A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain.

机构信息

Department of Molecular Biology, Genentech, South San Francisco, California 94080, USA.

出版信息

Nat Cell Biol. 2011 Dec 18;14(1):61-72. doi: 10.1038/ncb2410.

DOI:10.1038/ncb2410
PMID:22179047
Abstract

Using RNAi screening, proteomics, cell biological and mouse genetics approaches, we have identified a complex of nine proteins, seven of which are disrupted in human ciliopathies. A transmembrane component, TMEM231, localizes to the basal body before and independently of intraflagellar transport in a Septin 2 (Sept2)-regulated fashion. The localizations of TMEM231, B9D1 (B9 domain-containing protein 1) and CC2D2A (coiled-coil and C2 domain-containing protein 2A) at the transition zone are dependent on one another and on Sept2. Disruption of the complex in vitro causes a reduction in cilia formation and a loss of signalling receptors from the remaining cilia. Mouse knockouts of B9D1 and TMEM231 have identical defects in Sonic hedgehog (Shh) signalling and ciliogenesis. Strikingly, disruption of the complex increases the rate of diffusion into the ciliary membrane and the amount of plasma-membrane protein in the cilia. The complex that we have described is essential for normal cilia function and acts as a diffusion barrier to maintain the cilia membrane as a compartmentalized signalling organelle.

摘要

利用 RNAi 筛选、蛋白质组学、细胞生物学和小鼠遗传学方法，我们鉴定出了一个由九种蛋白质组成的复合物，其中七种在人类纤毛病中发生了突变。一种跨膜成分 TMEM231 在动粒蛋白 2（Sept2）调控下，在中心体组装之前以独立于内鞭毛运输的方式定位于基体。TMEM231、B9D1（B9 结构域蛋白 1）和 CC2D2A（卷曲螺旋和 C2 结构域蛋白 2A）在过渡区的定位相互依赖，并依赖于 Sept2。体外破坏复合物会导致纤毛形成减少，以及剩余纤毛上的信号受体丢失。B9D1 和 TMEM231 的小鼠敲除在 Sonic hedgehog（Shh）信号和纤毛发生中具有相同的缺陷。引人注目的是，复合物的破坏会增加扩散进入纤毛膜的速度和纤毛中质膜蛋白的量。我们所描述的复合物对于正常的纤毛功能是必不可少的，并且作为扩散屏障来维持纤毛膜作为一个分隔的信号细胞器。

相似文献

[1]
A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain.

Nat Cell Biol. 2011-12-18

[2]
A septin diffusion barrier at the base of the primary cilium maintains ciliary membrane protein distribution.

Science. 2010-6-17

[3]
Formation of the B9-domain protein complex MKS1-B9D2-B9D1 is essential as a diffusion barrier for ciliary membrane proteins.

Mol Biol Cell. 2020-9-15

[4]
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Nat Commun. 2017-1-30

[5]
Balancing the length of the distal tip by septins is key for stability and signalling function of primary cilia.

EMBO J. 2022-1-4

[6]
A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition.

Nat Genet. 2011-7-3

[7]
TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone.

J Cell Biol. 2015-4-13

[8]
The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking.

J Cell Biol. 2012-6-11

[9]
Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects.

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[10]
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引用本文的文献

[1]
Borg3 controls septin polymerization for primary cilia formation.

iScience. 2025-5-12

[2]
Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis.

Nat Commun. 2025-5-28

[3]
A tale of Rabs and the exocyst complex in ciliary trafficking and biogenesis.

Front Cell Dev Biol. 2025-5-6

[4]
Identification of de novo variants in KCTD10 as a proposed cause for multiple congenital anomalies.

HGG Adv. 2025-3-21

[5]
Mechanisms of cilia regeneration in Xenopus multiciliated epithelium in vivo.

EMBO Rep. 2025-4

[6]
High-throughput tracking enables systematic phenotyping and drug repurposing in disease models.

Elife. 2025-1-8

[7]
Septins as key players in spermatogenesis, fertilisation and pre-implantation embryogenic cytoplasmic dynamics.

Cell Commun Signal. 2024-10-28

[8]
Two functional forms of the Meckel-Gruber syndrome protein TMEM67 generated by proteolytic cleavage by ADAMTS9 mediate Wnt signaling and ciliogenesis.

bioRxiv. 2024-9-5

[9]
Molecular and structural perspectives on protein trafficking to the primary cilium membrane.

Biochem Soc Trans. 2024-6-26

[10]
Genetic mutation of results in male infertility due to abnormal sperm tail composition.

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本文引用的文献

[1]
The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking.

Hum Mol Genet. 2011-8-4

[2]
Disruption of a ciliary B9 protein complex causes Meckel syndrome.

Am J Hum Genet. 2011-7-15

[3]
A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition.

Nat Genet. 2011-7-3

[4]
Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways.

Cell. 2011-5-13

[5]
B9D1 is revealed as a novel Meckel syndrome (MKS) gene by targeted exon-enriched next-generation sequencing and deletion analysis.

Hum Mol Genet. 2011-4-14

[6]
A hierarchy of signals regulates entry of membrane proteins into the ciliary membrane domain in epithelial cells.

J Cell Biol. 2011-3-28

[7]
MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis.

J Cell Biol. 2011-3-21

[8]
NPHP4 is necessary for normal photoreceptor ribbon synapse maintenance and outer segment formation, and for sperm development.

Hum Mol Genet. 2010-11-15

[9]
Disruption of Mks1 localization to the mother centriole causes cilia defects and developmental malformations in Meckel-Gruber syndrome.

Dis Model Mech. 2010-11-2

[10]
A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes.

J Cell Biol. 2010-10-18

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