MKS1 interacts with components of the ubiquitin-proteasome pathway to regulate ciliogenesis and multiple signalling pathways

摘要

MKS1, a ciliary protein containing a B9 domain of unknownfunction, plays an important role in ciliogenesis.Mutation of the MKS1 gene causes the neonatal lethalmulti-organ developmental condition Meckel-Gruber syndrome,characterized by severe ciliary defects and disruptionof both Wnt and Shh signalling. We have performed ayeast two-hybrid screen for the MKS1 B9 domain andidentified and validated interactions between MKS1, andboth an E2 ubiquitin conjugating enzyme and an E3 ubiqutinligase. Previous studies have shown the importance ofthe basal body in regulating Wnt signalling through selectiveproteolysis and the study of the MKS1 protein offersadditional mechanistic insight into this process. We presentevidence that the role of MKS1 in ciliogenesis anddevelopmental signalling is mediated by targeted proteindegradation. Work on a newly characterised Mks1 mutantmouse also provides further insight into the role of thisparticular ciliary protein normal processes of in vivo developmentalsignalling regulation and its disruption inMeckel-Gruber syndrome.