Rbfox Proteins Regulate Splicing as Part of a Large Multiprotein Complex LASR.
Rbfox proteins control alternative splicing and posttranscriptional regulation in mammalian brain and are implicated in neurological disease. These proteins recognize the RNA sequence (U)GCAUG, but their structures and diverse roles imply a variety of protein-protein interactions. We find that nuclear Rbfox proteins are bound within a large assembly of splicing regulators (LASR), a multimeric complex containing the proteins hnRNP M, hnRNP H, hnRNP C, Matrin3, NF110/NFAR-2, NF45, and DDX5, all approximately equimolar to Rbfox. We show that splicing repression mediated by hnRNP M is stimulated by Rbfox. Virtually all the intron-bound Rbfox is associated with LASR, and hnRNP M motifs are enriched adjacent to Rbfox crosslinking sites in vivo. These findings demonstrate that Rbfox proteins bind RNA with a defined set of cofactors and affect a broader set of exons than previously recognized. The function of this multimeric LASR complex has implications for deciphering the regulatory codes controlling splicing networks.
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Andrey
A
Damianov
Molecular Biology Interdepartmental Ph.D. Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Yi
Y
Ying
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Chia-Ho
CH
Lin
Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Ji-Ann
JA
Lee
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Diana
D
Tran
Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Ajay A
AA
Vashisht
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Emad
E
Bahrami-Samani
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Yi
Y
Xing
Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Kelsey C
KC
Martin
Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
James A
JA
Wohlschlegel
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dougb@microbio.ucla.edu.
Douglas L
DL
Black
D020413:3' Untranslated Regions; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D005091:Exons; D057809:HEK293 Cells; D006801:Humans; D007438:Introns; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D012322:RNA Precursors / Q000378:metabolism; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000378:metabolism*
D020413:3' Untranslated Regions; D046912:Multiprotein Complexes; D012322:RNA Precursors; D016601:RNA-Binding Proteins