title: A U1 snRNP-specific assembly pathway reveals the SMN complex as a versatile hub for RNP exchange.
abstract: Despite equal snRNP stoichiometry in spliceosomes, U1 snRNP (U1) is typically the most abundant vertebrate snRNP. Mechanisms regulating U1 overabundance and snRNP repertoire are unknown. In Sm-core assembly, a key snRNP-biogenesis step mediated by the SMN complex, the snRNA-specific RNA-binding protein (RBP) Gemin5 delivers pre-snRNAs, which join SMN-Gemin2-recruited Sm proteins. We show that the human U1-specific RBP U1-70K can bridge pre-U1 to SMN-Gemin2-Sm, in a Gemin5-independent manner, thus establishing an additional and U1-exclusive Sm core-assembly pathway. U1-70K hijacks SMN-Gemin2-Sm, enhancing Sm-core assembly on U1s and inhibiting that on other snRNAs, thereby promoting U1 overabundance and regulating snRNP repertoire. SMN-Gemin2's ability to facilitate transactions between different RBPs and RNAs explains its multi-RBP valency and the myriad transcriptome perturbations associated with SMN deficiency in neurodegenerative spinal muscular atrophy. We propose that SMN-Gemin2 is a versatile hub for RNP exchange that functions broadly in RNA metabolism.
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Byung Ran
authors.initials: BR
authors.lastname: So
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Wan
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Zhenxi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Pilong
authors.initials: P
authors.lastname: Li
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Babiash
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Jingqi
authors.initials: J
authors.lastname: Duan
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Ihab
authors.initials: I
authors.lastname: Younis
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Gideon
authors.initials: G
authors.lastname: Dreyfuss
mesh_terms: D006801:Humans; D053858:Metabolic Networks and Pathways; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000737:chemistry / Q000378:metabolism*; D055532:SMN Complex Proteins / Q000378:metabolism
chemical_list: C108381:GEMIN2 protein, human; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D017412:Ribonucleoprotein, U1 Small Nuclear; D055532:SMN Complex Proteins
references.citation: Nat Genet. 1998 May;19(1):63-6
references.pmid: 9590291
references.citation: Hum Mol Genet. 2000 Nov 22;9(19):2869-77
references.pmid: 11092763
references.citation: Mol Cell Biol. 1999 Oct;19(10):6554-65
references.pmid: 10490595
references.citation: Mol Cell Biol. 2005 Jul;25(13):5543-51
references.pmid: 15964810
references.citation: Mol Cell. 2006 Jul 21;23(2):273-9
references.pmid: 16857593
references.citation: Mol Cell. 2007 Jan 12;25(1):71-83
references.pmid: 17218272
references.citation: Cold Spring Harb Symp Quant Biol. 2006;71:313-20
references.pmid: 17381311
references.citation: PLoS One. 2007;2(9):e921
references.pmid: 17895963
references.citation: Cell. 2008 May 16;133(4):585-600
references.pmid: 18485868
references.citation: Curr Opin Struct Biol. 2008 Jun;18(3):290-8
references.pmid: 18515081
references.citation: Mol Cell. 2008 Jul 25;31(2):244-54
references.pmid: 18657506
references.citation: Hum Mol Genet. 1998 Aug;7(8):1269-75
references.pmid: 9668169
references.citation: Semin Cell Dev Biol. 2014 Aug;32:22-9
references.pmid: 24769255
references.citation: EMBO J. 2001 Jan 15;20(1-2):187-96
references.pmid: 11226169
references.citation: Curr Opin Cell Biol. 2001 Jun;13(3):290-301
references.pmid: 11343899
references.citation: EMBO J. 2002 Mar 1;21(5):1188-96
references.pmid: 11867547
references.citation: Science. 2002 Nov 29;298(5599):1775-9
references.pmid: 12459587
references.citation: Mol Cell Biol. 2004 Apr;24(7):2747-56
references.pmid: 15024064
references.citation: Trends Cell Biol. 2004 May;14(5):226-32
references.pmid: 15130578
references.citation: Cell. 1983 Jun;33(2):509-18
references.pmid: 6190573
references.citation: Annu Rev Genet. 1988;22:387-419
references.pmid: 2977088
references.citation: EMBO J. 1990 Apr;9(4):1237-44
references.pmid: 2138978
references.citation: Nature. 1994 Mar 10;368(6467):119-24
references.pmid: 8139654
references.citation: EMBO J. 1994 Sep 1;13(17):4113-25
references.pmid: 8076607
references.citation: Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):E3277-86
references.pmid: 25071210
references.citation: Elife. 2015;4. doi: 10.7554/eLife.04986
references.pmid: 25555158
references.citation: Nat Commun. 2015;6:6171
references.pmid: 25625564
references.citation: Cell. 2008 Oct 31;135(3):497-509
references.pmid: 18984161
references.citation: Mol Cell. 2009 Jan 16;33(1):1-13
references.pmid: 19150423
references.citation: Nature. 2009 Mar 26;458(7237):475-80
references.pmid: 19325628
references.citation: Nat Struct Mol Biol. 2009 May;16(5):486-91
references.pmid: 19377484
references.citation: Nat Rev Neurosci. 2009 Aug;10(8):597-609
references.pmid: 19584893
references.citation: Mol Cell. 2010 May 28;38(4):551-62
references.pmid: 20513430
references.citation: Bioessays. 2010 Dec;32(12):1077-89
references.pmid: 20954180
references.citation: Nature. 2010 Dec 2;468(7324):664-8
references.pmid: 20881964
references.citation: EMBO J. 2010 Dec 15;29(24):4172-84
references.pmid: 21113136
references.citation: Proc Natl Acad Sci U S A. 2011 May 17;108(20):8233-8
references.pmid: 21536904
references.citation: Nature. 2011 May 26;473(7348):536-9
references.pmid: 21516107
references.citation: Cold Spring Harb Perspect Biol. 2011 Jul;3(7). pii: a003707. doi: 10.1101/cshperspect.a003707
references.pmid: 21441581
references.citation: Cell. 2011 Aug 5;146(3):384-95
references.pmid: 21816274
references.citation: Wiley Interdiscip Rev RNA. 2011 Sep-Oct;2(5):718-31
references.pmid: 21823231
references.citation: Mol Cell. 2011 Sep 16;43(6):927-39
references.pmid: 21925381
references.citation: Nat Struct Mol Biol. 2011 Dec;18(12):1414-20
references.pmid: 22101937
references.citation: PLoS One. 2012;7(2):e30375
references.pmid: 22363433
references.citation: Cell. 2012 Jul 6;150(1):53-64
references.pmid: 22770214
references.citation: Cell Rep. 2012 Oct 25;2(4):799-806
references.pmid: 23022481
references.citation: Nucleic Acids Res. 2013 Jan;41(2):1255-72
references.pmid: 23221635
references.citation: Genome Res. 2013 Feb;23(2):281-91
references.pmid: 23070852
references.citation: EMBO Mol Med. 2013 Feb;5(2):221-34
references.pmid: 23255347
references.citation: Mol Cell. 2013 Feb 21;49(4):692-703
references.pmid: 23333303
references.citation: Nature. 2013 Jul 18;499(7458):360-3
references.pmid: 23792564
references.citation: Elife. 2013;2:e00780
references.pmid: 23908766
references.citation: Nat Struct Mol Biol. 2013 Aug;20(8):923-8
references.pmid: 23851456
references.citation: Neuron. 2013 Aug 7;79(3):416-38
references.pmid: 23931993
references.citation: Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19348-53
references.pmid: 24191055
references.citation: Cell Rep. 2013 Dec 12;5(5):1187-95
references.pmid: 24332368
references.citation: Nat Rev Mol Cell Biol. 2014 Feb;15(2):108-21
references.pmid: 24452469