A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.
Primary cilium dysfunction underlies the pathogenesis of Bardet-Biedl syndrome (BBS), a genetic disorder whose symptoms include obesity, retinal degeneration, and nephropathy. However, despite the identification of 12 BBS genes, the molecular basis of BBS remains elusive. Here we identify a complex composed of seven highly conserved BBS proteins. This complex, the BBSome, localizes to nonmembranous centriolar satellites in the cytoplasm but also to the membrane of the cilium. Interestingly, the BBSome is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Strikingly, Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Conversely, preventing Rab8(GTP) production blocks ciliation in cells and yields characteristic BBS phenotypes in zebrafish. Our data reveal that BBS may be caused by defects in vesicular transport to the cilium.
Nachury
Maxence V
MV
Genentech, Inc., South San Francisco, CA 94080, USA. nachury@gene.com
Loktev
Alexander V
AV
Zhang
Qihong
Q
Westlake
Christopher J
CJ
Peränen
Johan
J
Merdes
Andreas
A
Slusarski
Diane C
DC
Scheller
Richard H
RH
Bazan
J Fernando
JF
Sheffield
Val C
VC
Jackson
Peter K
PK
D000595:Amino Acid Sequence; D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000378:metabolism*; D001692:Biological Transport; D002923:Cilia / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011485:Protein Binding; D021381:Protein Transport; D015027:Zebrafish; D020691:rab GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*
D020558:GTP Phosphohydrolases; C082377:RAB8A protein, human; D020691:rab GTP-Binding Proteins