The CHARGE Syndrome-associated Protein FAM172A Controls AGO2 Nuclear Import

Overview

Journal Life Sci Alliance

Specialties Biochemistry
Biology
Cell Biology
Molecular Biology

Date 2023 May 23

PMID 37221016

Authors

Sephora Sallis

Felix-Antoine Berube-Simard

Benoit Grondin

Elizabeth Leduc

Fatiha Azouz

Catherine Belanger

Nicolas Pilon

Affiliations

Soon will be listed here.

Abstract

CHARGE syndrome is a neural crest-related disorder mainly caused by mutation of the chromatin remodeler-coding gene Alternative causes include mutation of other chromatin and/or splicing factors. One of these additional players is the poorly characterized FAM172A, which we previously found in a complex with CHD7 and the small RNA-binding protein AGO2 at the chromatin-spliceosome interface. Focusing on the FAM172A-AGO2 interplay, we now report that FAM172A is a direct binding partner of AGO2 and, as such, one of the long sought-after regulators of AGO2 nuclear import. We show that this FAM172A function mainly relies on its classical bipartite nuclear localization signal and associated canonical importin-α/β pathway, being enhanced by CK2-induced phosphorylation and abrogated by a CHARGE syndrome-associated missense mutation. Overall, this study thus strengthens the notion that noncanonical nuclear functions of AGO2 and associated regulatory mechanisms might be clinically relevant.

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References

Meng Y, Ma X, Li J, Ito H, Oracz K, Cai J . The novel activity of Argonautes in intron splicing: A transcriptome-wide survey in plants. J Plant Physiol. 2022; 270:153632. DOI: 10.1016/j.jplph.2022.153632. View

Sun H, Cui R, Zhou J, Teng K, Hsiao Y, Nakanishi K . ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5. Cancer Cell. 2016; 30(5):723-736. PMC: 5127275. DOI: 10.1016/j.ccell.2016.10.001. View

Berube-Simard F, Pilon N . Molecular dissection of CHARGE syndrome highlights the vulnerability of neural crest cells to problems with alternative splicing and other transcription-related processes. Transcription. 2018; 10(1):21-28. PMC: 6351119. DOI: 10.1080/21541264.2018.1521213. View

Taliaferro J, Aspden J, Bradley T, Marwha D, Blanchette M, Rio D . Two new and distinct roles for Drosophila Argonaute-2 in the nucleus: alternative pre-mRNA splicing and transcriptional repression. Genes Dev. 2013; 27(4):378-89. PMC: 3589555. DOI: 10.1101/gad.210708.112. View

Vissers L, van Ravenswaaij C, Admiraal R, Hurst J, de Vries B, Janssen I . Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. 2004; 36(9):955-7. DOI: 10.1038/ng1407. View

Sharma N, Wang X, Majerciak V, Ajiro M, Kruhlak M, Meyers C . Cell Type- and Tissue Context-dependent Nuclear Distribution of Human Ago2. J Biol Chem. 2015; 291(5):2302-9. PMC: 4732213. DOI: 10.1074/jbc.C115.695049. View

Kobayashi J, Matsuura Y . Structural basis for cell-cycle-dependent nuclear import mediated by the karyopherin Kap121p. J Mol Biol. 2013; 425(11):1852-1868. DOI: 10.1016/j.jmb.2013.02.035. View

Pilon N . Treatment and Prevention of Neurocristopathies. Trends Mol Med. 2021; 27(5):451-468. DOI: 10.1016/j.molmed.2021.01.009. View

Chu Y, Yokota S, Liu J, Kilikevicius A, Johnson K, Corey D . Argonaute binding within human nuclear RNA and its impact on alternative splicing. RNA. 2021; 27(9):991-1003. PMC: 8370746. DOI: 10.1261/rna.078707.121. View

10.

Sun Q, Carrasco Y, Hu Y, Guo X, Mirzaei H, MacMillan J . Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1. Proc Natl Acad Sci U S A. 2013; 110(4):1303-8. PMC: 3557022. DOI: 10.1073/pnas.1217203110. View

11.

Hudry B, Viala S, Graba Y, Merabet S . Visualization of protein interactions in living Drosophila embryos by the bimolecular fluorescence complementation assay. BMC Biol. 2011; 9:5. PMC: 3041725. DOI: 10.1186/1741-7007-9-5. View

12.

Hutvagner G, Simard M . Argonaute proteins: key players in RNA silencing. Nat Rev Mol Cell Biol. 2007; 9(1):22-32. DOI: 10.1038/nrm2321. View

13.

Hoffman E, Frey B, Smith L, Auble D . Formaldehyde crosslinking: a tool for the study of chromatin complexes. J Biol Chem. 2015; 290(44):26404-11. PMC: 4646298. DOI: 10.1074/jbc.R115.651679. View

14.

Pilon N . Pigmentation-based insertional mutagenesis is a simple and potent screening approach for identifying neurocristopathy-associated genes in mice. Rare Dis. 2016; 4(1):e1156287. PMC: 4838316. DOI: 10.1080/21675511.2016.1156287. View

15.

Ohrt T, Mutze J, Staroske W, Weinmann L, Hock J, Crell K . Fluorescence correlation spectroscopy and fluorescence cross-correlation spectroscopy reveal the cytoplasmic origination of loaded nuclear RISC in vivo in human cells. Nucleic Acids Res. 2008; 36(20):6439-49. PMC: 2582625. DOI: 10.1093/nar/gkn693. View

16.

Sarshad A, Juan A, Correa Muler A, Anastasakis D, Wang X, Genzor P . Argonaute-miRNA Complexes Silence Target mRNAs in the Nucleus of Mammalian Stem Cells. Mol Cell. 2018; 71(6):1040-1050.e8. PMC: 6690358. DOI: 10.1016/j.molcel.2018.07.020. View

17.

Doi N, Zenno S, Ueda R, Ohki-Hamazaki H, Ui-Tei K, Saigo K . Short-interfering-RNA-mediated gene silencing in mammalian cells requires Dicer and eIF2C translation initiation factors. Curr Biol. 2003; 13(1):41-6. DOI: 10.1016/s0960-9822(02)01394-5. View

18.

Schraivogel D, Meister G . Import routes and nuclear functions of Argonaute and other small RNA-silencing proteins. Trends Biochem Sci. 2014; 39(9):420-31. DOI: 10.1016/j.tibs.2014.07.004. View

19.

Castanotto D, Zhang X, Alluin J, Zhang X, Ruger J, Armstrong B . A stress-induced response complex (SIRC) shuttles miRNAs, siRNAs, and oligonucleotides to the nucleus. Proc Natl Acad Sci U S A. 2018; 115(25):E5756-E5765. PMC: 6016802. DOI: 10.1073/pnas.1721346115. View

20.

Kodama Y, Hu C . Bimolecular fluorescence complementation (BiFC): a 5-year update and future perspectives. Biotechniques. 2012; 53(5):285-98. DOI: 10.2144/000113943. View