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Open AccessArticle

Interferon-β Stimulation Elicited by the Influenza Virus Is Regulated by the Histone Methylase Dot1L through the RIG-I-TRIM25 Signaling Axis

1
Departamento de Biologia Molecular y Celular, Centro Nacional de Biotecnología, C.S.I.C. Darwin 3, Cantoblanco, 28049 Madrid, Spain
2
Ciber de Enfermedades Respiratorias CIBERES, 28029 Madrid, Spain
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Microbiology Section, Dpto. CC, Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU San Pablo, CEU Universities, Boadilla del Monte, 28660 Madrid, Spain
4
Instituto de Medicina Molecular Aplicada (IMMA), Universidad CEU San Pablo, Pablo-CEU, CEU Universities, Boadilla del Monte, 28660 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(3), 732; https://doi.org/10.3390/cells9030732
Received: 11 February 2020 / Revised: 8 March 2020 / Accepted: 10 March 2020 / Published: 16 March 2020
Influenza virus infection increases the methylation of lysine 79 of histone 3 catalyzed by the Dot1L enzyme. The role of Dot1L against infections was highlighted by an increase of influenza A and vesicular stomatitis virus replication in Dot1L-inhibited cells mediated by a decreased antiviral response. Interferon-beta (IFN-β) reporter assays indicate that Dot1L is involved in the control of retinoic acid-inducible gene-I protein (RIG-I) signaling. Accordingly, Dot1L inhibition decreases the IFN-β promoter stimulation and RIG-I- mitochondria-associated viral sensor (RIG-I-MAVS) association upon viral infection. Replication of an influenza A virus lacking NS1 (delNS1), incapable of counteracting the antiviral response, is not affected by Dot1L inhibition. Consequently, RIG-I-MAVS association and nuclear factor–κB (NF-κB) nuclear translocation, are not affected by the Dot1L inhibition in delNS1 infected cells. Restoration of NS1 expression in trans also reinstated Dot1L as a regulator of the RIG-I-dependent signaling in delNS1 infections. Interferon-inducible E3 ligase tripartite motif-containing protein 25 (TRIM25) expression increases in influenza virus infected cells, but Dot1L inhibition reduces both the TRIM25 expression and TRIM25 protein levels. TRIM25 overexpression reverses the defective innate response mediated by Dot1L inhibition elicited upon virus infection or by overexpression of RIG-I signaling intermediates. Thus, TRIM25 is a control point of the RIG-I recognition pathway controlled by Dot1L and may have a general role in RNA viruses recognized by the RIG-I sensor. View Full-Text
Keywords: Dot1L histone methylase; TRIM25; influenza virus; RIG-I signaling; Type I IFN; RNA virus infection Dot1L histone methylase; TRIM25; influenza virus; RIG-I signaling; Type I IFN; RNA virus infection
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Marcos-Villar, L.; Nistal-Villan, E.; Zamarreño, N.; Garaigorta, U.; Gastaminza, P.; Nieto, A. Interferon-β Stimulation Elicited by the Influenza Virus Is Regulated by the Histone Methylase Dot1L through the RIG-I-TRIM25 Signaling Axis. Cells 2020, 9, 732.

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