title: SUMOylation promotes PML degradation during encephalomyocarditis virus infection.
abstract: The promyelocytic leukemia (PML) protein is expressed in the diffuse nuclear fraction of the nucleoplasm and in matrix-associated structures, known as nuclear bodies (NBs). PML NB formation requires the covalent modification of PML to SUMO. The noncovalent interactions of SUMO with PML based on the identification of a SUMO-interacting motif within PML seem to be required for further recruitment within PML NBs of SUMOylated proteins. RNA viruses whose replication takes place in the cytoplasm and is inhibited by PML have developed various strategies to counteract the antiviral defense mediated by PML NBs. We show here that primary fibroblasts derived from PML knockout mice are more sensitive to infection with encephalomyocarditis virus (EMCV), suggesting that the absence of PML results in an increase in EMCV replication. Also, we found that EMCV induces a decrease in PML protein levels both in interferon-treated cells and in PMLIII-expressing cells. Reduction of PML was carried out by the EMCV 3C protease. Indeed, at early times postinfection, EMCV induced PML transfer from the nucleoplasm to the nuclear matrix and PML conjugation to SUMO-1, SUMO-2, and SUMO-3, leading to an increase in PML body size where the viral protease 3C and the proteasome component were found colocalizing with PML within the NBs. This process was followed by PML degradation occurring in a proteasome- and SUMO-dependent manner and did not involve the SUMO-interacting motif of PML. Together, these findings reveal a new mechanism evolved by EMCV to antagonize the PML pathway in the interferon-induced antiviral defense.
authors.affiliation: Université Paris Descartes, 75006 Paris, France.
authors.forename: Bouchra
authors.initials: B
authors.lastname: El McHichi
authors.forename: Tarik
authors.initials: T
authors.lastname: Regad
authors.forename: Mohamed-Ali
authors.initials: MA
authors.lastname: Maroui
authors.forename: Manuel S
authors.initials: MS
authors.lastname: Rodriguez
authors.forename: Aleksey
authors.initials: A
authors.lastname: Aminev
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gerbaud
authors.forename: Nicolas
authors.initials: N
authors.lastname: Escriou
authors.forename: Laurent
authors.initials: L
authors.lastname: Dianoux
authors.forename: Mounira K
authors.initials: MK
authors.lastname: Chelbi-Alix
mesh_terms: D000818:Animals; D016466:CHO Cells; D018188:Cardiovirus Infections / Q000378:metabolism* / Q000821:virology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004686:Encephalomyocarditis virus / Q000502:physiology*; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human
references.citation: J Virol. 2001 Jul;75(13):6204-8
references.pmid: 11390623
references.citation: J Exp Med. 2001 Jun 18;193(12):1361-71
references.pmid: 11413191
references.citation: Virus Res. 2003 Sep;95(1-2):45-57
references.pmid: 12921995
references.citation: J Virol. 1992 Mar;66(3):1602-9
references.pmid: 1310768
references.citation: Virus Res. 2003 Sep;95(1-2):59-73
references.pmid: 12921996
references.citation: J Biol Chem. 1998 Oct 9;273(41):26675-82
references.pmid: 9756909
references.citation: Cell. 1991 Aug 23;66(4):675-84
references.pmid: 1652369
references.citation: Oncogene. 2001 Oct 29;20(49):7234-42
references.pmid: 11704851
references.citation: J Virol. 1998 May;72(5):3819-26
references.pmid: 9557665
references.citation: J Virol. 2006 Mar;80(6):2705-17
references.pmid: 16501080
references.citation: Biochimie. 2007 Jun-Jul;89(6-7):819-30
references.pmid: 17343971
references.citation: Cell. 2000 Apr 14;101(2):173-85
references.pmid: 10786833
references.citation: Nat Rev Immunol. 2008 Jul;8(7):559-68
references.pmid: 18575461
references.citation: Biochimie. 2007 Jun-Jul;89(6-7):713-8
references.pmid: 17544197
references.citation: J Virol. 1989 Mar;63(3):1054-8
references.pmid: 2536819
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3978-83
references.pmid: 9108090
references.citation: J Virol. 2009 Feb;83(4):1941-51
references.pmid: 19073724
references.citation: J Virol. 2009 May;83(10):5168-80
references.pmid: 19279115
references.citation: Cell. 1994 Jan 28;76(2):333-43
references.pmid: 8293467
references.citation: J Interferon Cytokine Res. 2006 May;26(5):271-80
references.pmid: 16689655
references.citation: J Gen Virol. 2004 Oct;85(Pt 10):2969-2979
references.pmid: 15448360
references.citation: J Virol. 1998 Feb;72(2):1043-51
references.pmid: 9444998
references.citation: J Virol. 2002 Apr;76(8):3810-8
references.pmid: 11907221
references.citation: Cell Microbiol. 2006 Mar;8(3):365-74
references.pmid: 16469050
references.citation: J Biol Chem. 2008 Sep 12;283(37):25660-25670
references.pmid: 18635538
references.citation: Proc Natl Acad Sci U S A. 1987 Jan;84(1):21-5
references.pmid: 3467351
references.citation: Oncogene. 2005 Jan 20;24(4):605-15
references.pmid: 15580300
references.citation: J Gen Virol. 2009 Mar;90(Pt 3):536-545
references.pmid: 19218198
references.citation: Oncogene. 2001 Oct 29;20(49):7274-86
references.pmid: 11704856
references.citation: Cell. 2006 Jul 28;126(2):269-83
references.pmid: 16873060
references.citation: Mol Cell. 2005 Apr 1;18(1):1-12
references.pmid: 15808504
references.citation: Oncogene. 2002 Nov 14;21(52):7957-70
references.pmid: 12439746
references.citation: Oncogene. 2001 Oct 29;20(49):7223-33
references.pmid: 11704850
references.citation: J Biol Chem. 2009 Jun 12;284(24):16595-16608
references.pmid: 19380586
references.citation: J Virol. 2007 Dec;81(23):13067-74
references.pmid: 17728235
references.citation: J Gen Virol. 1995 Aug;76 ( Pt 8):1999-2007
references.pmid: 7636480
references.citation: J Virol. 1980 Aug;35(2):414-9
references.pmid: 6255181
references.citation: Nat Genet. 1998 Nov;20(3):266-72
references.pmid: 9806545
references.citation: J Biol Chem. 2001 Sep 21;276(38):35368-74
references.pmid: 11451954
references.citation: Virology. 2009 Sep 1;391(2):171-6
references.pmid: 19628239
references.citation: Nat Rev Mol Cell Biol. 2009 Aug;10(8):564-8
references.pmid: 19474794
references.citation: Virology. 2007 Apr 10;360(2):350-63
references.pmid: 17150238
references.citation: Virus Genes. 1996;13(2):99-110
references.pmid: 8972564
references.citation: J Virol. 1980 Sep;35(3):732-40
references.pmid: 6252335
references.citation: Leukemia. 1995 Dec;9(12):2027-33
references.pmid: 8609713
references.citation: Cell Microbiol. 2010 Mar;12(3):310-7
references.pmid: 19863558
references.citation: Mol Cell. 2006 Nov 3;24(3):331-9
references.pmid: 17081985
references.citation: J Virol. 1974 Sep;14(3):598-610
references.pmid: 4368674
references.citation: EMBO J. 2001 Jul 2;20(13):3495-505
references.pmid: 11432836
references.citation: Nat Rev Drug Discov. 2007 Dec;6(12):975-90
references.pmid: 18049472
references.citation: EMBO J. 1994 Mar 1;13(5):1073-83
references.pmid: 8131741
references.citation: Cell Microbiol. 2007 Dec;9(12):2921-30
references.pmid: 17991048
references.citation: J Virol. 2006 Sep;80(17):8582-92
references.pmid: 16912307
references.citation: Oncogene. 1995 Dec 21;11(12):2565-73
references.pmid: 8545113