FAM172A controls the nuclear import and alternative splicing function of AGO2

Abstract

AbstractThe poorly characterized protein FAM172A is mutated in some individuals affected by a disorder of neural crest development called CHARGE syndrome. We also know that FAM172A can interact with the main CHARGE syndrome-associated protein CHD7 and the small RNA-binding protein AGO2 at the chromatin-spliceosome interface. Focusing on this intriguing FAM172A-AGO2 interaction, we now report that FAM172A is one of the long sought-after regulator of AGO2 nuclear import. This FAM172A function relies on its nuclear localization signal, being enhanced by CK2-mediated phosphorylation and abrogated by a CHARGE syndrome-associated missense mutation. Accordingly, Fam172a and Ago2 genetically interact in mice, and neural crest-specific depletion of Ago2 is sufficient to phenocopy CHARGE syndrome without impacting post-transcriptional gene silencing. Rapamycin-mediated rescue suggests that observed morphological anomalies are instead due to alternative splicing defects. This work thus demonstrates that non-canonical nuclear functions of AGO2 and associated regulatory mechanisms may be clinically relevant.