Epstein-Barr Virus SM protein utilizes cellular splicing factor SRp20 to mediate alternative splicing.
Epstein-Barr virus (EBV) SM protein is an essential nuclear protein produced during the lytic cycle of EBV replication. SM is an RNA-binding protein with multiple mechanisms of action. SM enhances the expression of EBV genes by stabilizing mRNA and facilitating nuclear export. SM also influences splicing of both EBV and cellular pre-mRNAs. SM modulates splice site selection of the host cell STAT1 pre-mRNA, directing utilization of a novel 5' splice site that is used only in the presence of SM. SM activates splicing in the manner of SR proteins but does not contain the canonical RS domains typical of cellular splicing factors. Affinity purification and mass spectrometry of SM complexes from SM-transfected cells led to the identification of the cellular SR splicing factor SRp20 as an SM-interacting protein. The regions of SM and SRp20 required for interaction were mapped by in vitro and in vivo assays. The SRp20 interaction was shown to be important for the effects of SM on alternative splicing by the use of STAT1 splicing assays. Overexpression of SRp20 enhanced SM-mediated alternative splicing and knockdown of SRp20 inhibited the SM effect on splicing. These data suggest a model whereby SM, a viral protein, recruits and co-opts the function of cellular SRp20 in alternative splicing.
Verma
Dinesh
D
Department of Medicine, University of Florida, Gainesville, FL 32610, USA.
Bais
Swarna
S
Gaillard
Melusine
M
Swaminathan
Sankar
S
D017398:Alternative Splicing; D002460:Cell Line; D020031:Epstein-Barr Virus Infections / Q000378:metabolism* / Q000821:virology; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
C068382:BRLF1 protein, Human herpesvirus 4; D017874:Immediate-Early Proteins; D016601:RNA-Binding Proteins; C491388:SRSF3 protein, human; D015534:Trans-Activators; D000068103:Serine-Arginine Splicing Factors
J Biol Chem. 1997 Nov 7;272(45):28582-9
9353323
J Virol. 2002 Oct;76(19):9635-44
12208942
J Virol. 1999 May;73(5):4090-100
10196305
J Virol. 2003 Mar;77(6):3690-701
12610144
J Virol. 1998 Nov;72(11):8485-92
9765385
J Virol. 2000 Jul;74(13):6068-76
10846090
J Virol. 2009 Nov;83(22):11635-44
19726500
J Virol. 2009 Aug;83(16):8041-50
19515786
Science. 2003 Dec 19;302(5653):2141-4
14684825
J Gen Virol. 1977 Jul;36(1):59-74
886304
J Proteome Res. 2004 May-Jun;3(3):463-8
15253427
PLoS Pathog. 2010 Mar 05;6(3):e1000799
20221435
Nat Rev Mol Cell Biol. 2009 Nov;10(11):741-54
19773805
Mol Cell. 2009 Apr 24;34(2):179-90
19394295
J Virol. 2001 Jul;75(13):6033-41
11390605
Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8852-7
9671768
J Virol. 1982 Dec;44(3):834-44
6294333
Nat Struct Mol Biol. 2007 Jul;14(7):597-603
17603499
J Med Virol. 2003 Mar;69(3):306-12
12526039
Blood. 2004 Oct 15;104(8):2475-83
15217838
Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5154-9
18364396
Science. 1997 Sep 12;277(5332):1630-5
9287210
J Virol. 2009 Dec;83(24):12759-68
19793817
Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9666-70
15210956
J Virol. 1998 Dec;72(12):9526-34
9811685
EMBO J. 2006 Nov 1;25(21):5126-37
17036044
EMBO J. 2003 Apr 1;22(7):1608-19
12660167
J Virol. 2004 Sep;78(17):9412-22
15308735
J Biol Chem. 2003 Jan 3;278(1):335-42
12403791
Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16286-91
15534216
J Biol Chem. 2003 Sep 26;278(39):37790-8
12857728
Genes Dev. 2006 Jul 1;20(13):1755-65
16766678
Mol Cell Biol. 1998 Apr;18(4):2205-17
9528792
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7673-8
8755534
J Virol. 1999 Aug;73(8):6872-81
10400785
Virology. 2010 Jun 5;401(2):155-64
20227104
J Virol. 2007 Apr;81(8):4058-69
17287267
RNA. 2000 Sep;6(9):1197-211
10999598
Mol Cell Biol. 1996 Jan;16(1):288-93
8524306
Mol Cell Biol. 1998 Sep;18(9):4977-85
9710581
J Virol. 2008 Jul;82(14):7180-8
18463151