Direct role of Bardet-Biedl syndrome proteins in transcriptional regulation.
Primary cilia are conserved organelles that play crucial roles as mechano- and chemosensors, as well as transducing signaling cascades. Consequently, ciliary dysfunction results in a broad range of phenotypes: the ciliopathies. Bardet-Biedl syndrome (BBS), a model ciliopathy, is caused by mutations in 16 known genes. However, the biochemical functions of the BBS proteins are not fully understood. Here we show that the BBS7 protein (localized in the centrosomes, basal bodies and cilia) probably has a nuclear role by virtue of the presence of a biologically confirmed nuclear export signal. Consistent with this observation, we show that BBS7 interacts physically with the polycomb group (PcG) member RNF2 and regulate its protein levels, probably through a proteasome-mediated mechanism. In addition, our data supports a similar role for other BBS proteins. Importantly, the interaction with this PcG member is biologically relevant because loss of BBS proteins leads to the aberrant expression of endogenous RNF2 targets in vivo, including several genes that are crucial for development and for cellular and tissue homeostasis. Our data indicate a hitherto unappreciated, direct role for the BBS proteins in transcriptional regulation and potentially expand the mechanistic spectrum that underpins the development of ciliary phenotypes in patients.
Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Montevideo, CP 11400,  Uruguay.
Cecilia
C
Gascue
Perciliz L
PL
Tan
Magdalena
M
Cardenas-Rodriguez
Gabriela
G
Libisch
Tamara
T
Fernandez-Calero
Yangfan P
YP
Liu
Soledad
S
Astrada
Carlos
C
Robello
Hugo
H
Naya
Nicholas
N
Katsanis
Jose L
JL
Badano
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003198:Computer Simulation; D003598:Cytoskeletal Proteins; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D049790:Nuclear Export Signals; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D015027:Zebrafish / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C473308:Bbs7 protein, human; D003598:Cytoskeletal Proteins; D049790:Nuclear Export Signals; D011506:Proteins; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human