title: Promyelocytic leukemia isoform IV confers resistance to encephalomyocarditis virus via the sequestration of 3D polymerase in nuclear bodies.
abstract: Promyelocytic leukemia (PML) protein is the organizer of nuclear matrix-associated nuclear bodies (NBs), and its conjugation to the small ubiquitin-like modifier (SUMO) is required for the formation of these structures. Several alternatively spliced PML transcripts from a single PML gene lead to the production of seven PML isoforms (PML isoform I [PMLI] to VII [PMLVII]), which all share a N-terminal region that includes the RBCC (RING, B boxes, and a α-helical coiled-coil) motif but differ in the C-terminal region. This diversity of PML isoforms determines the specific functions of each isoform. There is increasing evidence implicating PML in host antiviral defense and suggesting various strategies involving PML to counteract viral production. We reported that mouse embryonic fibroblasts derived from PML knockout mice are more sensitive than wild-type cells to infection with encephalomyocarditis virus (EMCV). Here, we show that stable expression of PMLIV or PMLIVa inhibited viral replication and protein synthesis, leading to a substantial reduction of EMCV multiplication. This protective effect required PMLIV SUMOylation and was not observed with other nuclear PML isoforms (I, II, III, V, and VI) or with the cytoplasmic PMLVII. We demonstrated that only PMLIV interacted with EMCV 3D polymerase (3Dpol) and sequestered it within PML NBs. The C-terminal region specific to PMLIV was required for both interaction with 3Dpol and the antiviral properties. Also, depletion of PMLIV by RNA interference significantly boosted EMCV production in interferon-treated cells. These findings indicate the mechanism by which PML confers resistance to EMCV. They also reveal a new pathway mediating the antiviral activity of interferon against EMCV.
authors: CNRS FRE3235, Université Paris Descartes, 45 rue des Saints Pères, 75006 Paris, France. mounira.chelbi-alix@parisdescartes.fr
authors: Mohamed Ali
authors: MA
authors: Maroui
authors: Mathieu
authors: M
authors: Pampin
authors: Mounira K
authors: MK
authors: Chelbi-Alix
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004686:Encephalomyocarditis virus / Q000201:enzymology* / Q000276:immunology*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D012321:DNA-Directed RNA Polymerases