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PMID:19625297

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Citation

Hsiao, YC, Tong, ZJ, Westfall, JE, Ault, JG, Page-McCaw, PS and Ferland, RJ (2009) Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking. Hum. Mol. Genet. 18:3926-41

Abstract

The primary non-motile cilium, a membrane-ensheathed, microtubule-bundled organelle, extends from virtually all cells and is important for development. Normal functioning of the cilium requires proper axoneme assembly, membrane biogenesis and ciliary protein localization, in tight coordination with the intraflagellar transport system and vesicular trafficking. Disruptions at any level can induce severe alterations in cell function, giving rise to a myriad of human genetic diseases known as ciliopathies. Here we show that the Abelson helper integration site 1 (Ahi1) gene, whose human ortholog is mutated in Joubert syndrome, regulates cilium formation via its interaction with Rab8a, a small GTPase critical for polarized membrane trafficking. We find that the Ahi1 protein localizes to a single centriole, the mother centriole, which becomes the basal body of the primary cilium. In order to determine whether Ahi1 functions in ciliogenesis, loss of function analysis of Ahi1 was performed in cell culture models of ciliogenesis. Knockdown of Ahi1 expression by shRNAi in cells or targeted deletion of Ahi1 (Ahi1 knockout mouse) leads to impairments in ciliogenesis. In Ahi1-knockdown cells, Rab8a is destabilized and does not properly localize to the basal body. Since Rab8a is implicated in vesicular trafficking, we next examined this process in Ahi1-knockdown cells. Defects in the trafficking of endocytic vesicles from the plasma membrane to the Golgi and back to the plasma membrane were observed in Ahi1-knockdown cells. Overall, our data indicate that the distribution and functioning of Rab8a is regulated by Ahi1, not only affecting cilium formation, but also vesicle transport.

Links

PubMed PMC2748898 Online version:10.1093/hmg/ddp335

Keywords

Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Animals; Cell Line; Cells, Cultured; Cilia/genetics; Cilia/metabolism; Female; Fibroblasts/metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Nervous System Diseases/genetics; Nervous System Diseases/metabolism; Protein Binding; Protein Transport; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Transport Vesicles/metabolism; rab GTP-Binding Proteins/genetics; rab GTP-Binding Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ODFP2

located_in

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RAB8A

located_in

GO:0097730: non-motile cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:28370)

Seeded From UniProt

complete

MOUSE:RAB8A

located_in

GO:0036064: ciliary basal body

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:28370)

Seeded From UniProt

complete

MOUSE:NIN

located_in

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AHI1

acts_upstream_of_or_within

GO:0016192: vesicle-mediated transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(EMAPA:28370)

Seeded From UniProt

complete

MOUSE:AHI1

located_in

GO:0097730: non-motile cilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:28370)

Seeded From UniProt

complete

MOUSE:AHI1

located_in

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000020)|part_of:(EMAPA:28370)

Seeded From UniProt

complete

MOUSE:AHI1

located_in

GO:0036064: ciliary basal body

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:28370)

Seeded From UniProt

complete

MOUSE:AHI1

acts_upstream_of_or_within

GO:1905515: non-motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(EMAPA:28370)

Seeded From UniProt

complete

MOUSE:AHI1

located_in

GO:0097730: non-motile cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AHI1

located_in

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000020)

Seeded From UniProt

complete

MOUSE:AHI1

located_in

GO:0036064: ciliary basal body

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0060271: cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AHI1

part_of

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000020)

Seeded From UniProt

complete

MOUSE:AHI1

part_of

GO:0005814: centriole

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000020)|part_of:(EMAPA:28370)

Seeded From UniProt

complete

MOUSE:AHI1

part_of

GO:0036064: ciliary basal body

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(EMAPA:28370)

Seeded From UniProt

complete

MOUSE:AHI1

acts_upstream_of_or_within

GO:0033365: protein localization to organelle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AHI1

acts_upstream_of_or_within

GO:0016192: vesicle-mediated transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(EMAPA:28370)

Seeded From UniProt

complete

MOUSE:AHI1

involved_in

GO:0016192: vesicle-mediated transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AHI1

part_of

GO:0097730: non-motile cilium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AHI1

part_of

GO:0036064: ciliary basal body

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AHI1

acts_upstream_of_or_within

GO:1905515: non-motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(EMAPA:28370)

Seeded From UniProt

complete

MOUSE:AHI1

part_of

GO:0097730: non-motile cilium

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(EMAPA:28370)

Seeded From UniProt

complete


See also

References

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