Disrupted IRF6-NME1/2 Complexes as a Cause of Cleft Lip/Palate

Mutations and common polymorphisms in interferon regulatory factor6 ( IRF6) are associated with both syndromic and nonsyndromic forms of cleft lip/palate (CLP). To date, much of the focus on this transcription factor has been on identifying its direct targets and the gene regulatory networkin which it operates. Notably, however, IRF6is found predominantly in the cytoplasm, with its import into the nucleus tightly regulated like other members of the IRF family. To provide further insight into the role of IRF6in the pathogenesis of CLP, we sought to identify direct IRF6protein interactors using a combination of yeast 2-hybrid screens and co-immunoprecipitation assays. Using this approach, we identified NME1 and NME2, well-known regulators of Rho-type GTPases, E-cadherin endocytosis, and epithelial junctional remodeling, as bona fide IRF6partner proteins. The NME proteins co-localize with IRF6in the cytoplasm of primary palatal epithelial cells in vivo, and their interaction with IRF6is significantly ...