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

• Main Authors: Laura Marcos-Villar, Estanislao Nistal-Villan, Noelia Zamarreño, Urtzi Garaigorta, Pablo Gastaminza, Amelia Nieto
• Format: Article
• Language: English
• Published: MDPI AG 2020-03-01
• Series: Cells
• Subjects: dot1l histone methylase; trim25; influenza virus; rig-i signaling; type i ifn; rna virus infection
• Online Access: https://www.mdpi.com/2073-4409/9/3/732

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-&#946;) 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-&#946; 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&#8722;&#954;B (NF-&#954;B) nuclear translocation, are not affected by the Dot1L inhibition in delNS1 infected cells. Restoration of NS1 expression in <i>trans</i> also reinstated Dot1L as a regulator of the RIG-I-dependent signaling in delNS1 infections. Interferon-inducible E3 ligase tripartite motif-containing protein 25 (<i>TRIM25</i>) expression increases in influenza virus infected cells, but Dot1L inhibition reduces both the <i>TRIM25</i> expression and TRIM25 protein levels. <i>TRIM25</i> 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.