The DEAH-Box RNA Helicase DHX15 Activates NF-κB and MAPK Signaling Downstream of MAVS During Antiviral Responses

Sci. Signal., 29 April 2014
Vol. 7, Issue 323, p. ra40
DOI: 10.1126/scisignal.2004841

The DEAH-Box RNA Helicase DHX15 Activates NF-κB and MAPK Signaling Downstream of MAVS During Antiviral Responses

  1. Kenta Mosallanejad1,
  2. Yusuke Sekine1,
  3. Seiko Ishikura-Kinoshita1,
  4. Kazuo Kumagai2,3,
  5. Tetsuo Nagano2,
  6. Atsushi Matsuzawa1,
  7. Kohsuke Takeda1,4,
  8. Isao Naguro1, and
  9. Hidenori Ichijo1,2,*
  1. 1Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
  2. 2Open Innovation Center for Drug Discovery, The University of Tokyo, Tokyo 113-0033, Japan.
  3. 3Genomic Science Laboratories, Dainippon Sumitomo Pharma Co. Ltd., Osaka 554-0022, Japan.
  4. 4Division of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
  1. *Corresponding author. E-mail: ichijo{at}mol.f.u-tokyo.ac.jp

Abstract

During infection with an RNA virus, the DExD/H-box RNA helicases RIG-I (retinoic acid–inducible gene I) and MDA5 (melanoma differentiation–associated gene 5) activate the interferon regulatory factor 3 (IRF3), nuclear factor κB (NF-κB), c-Jun amino-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways through an unknown mechanism involving the adaptor protein MAVS (mitochondrial antiviral signaling). We used a Drosophila misexpression screen to identify DEAH-box polypeptide 15 (DHX15) as an activator of the p38 MAPK pathway. Human DHX15 contributed to the activation of the NF-κB, JNK, and p38 MAPK pathways, but not the IRF3 pathway, in response to the synthetic double-stranded RNA analog poly(I:C) (polyinosinic-polycytidylic acid), and DHX15 was required for optimal cytokine production in response to poly(I:C) and infection with RNA virus. DHX15 physically interacted with MAVS and mediated the MAVS-dependent activation of the NF-κB and MAPK pathways. Furthermore, DHX15 was required for poly(I:C)- and RNA virus–dependent, MAVS-mediated apoptosis. Thus, our findings indicate that, in RIG-I–like receptor signaling, DHX15 specifically stimulates the NF-κB and MAPK pathways downstream of MAVS and contributes to MAVS-mediated cytokine production and apoptosis.

Citation:

K. Mosallanejad, Y. Sekine, S. Ishikura-Kinoshita, K. Kumagai, T. Nagano, A. Matsuzawa, K. Takeda, I. Naguro, and H. Ichijo, The DEAH-Box RNA Helicase DHX15 Activates NF-κB and MAPK Signaling Downstream of MAVS During Antiviral Responses. Sci. Signal. 7, ra40 (2014).

Phosphoproteomics Combined with Quantitative 14-3-3-affinity Capture Identifies SIRT1 and RAI as Novel Regulators of Cytosolic Double-stranded RNA Recognition Pathway
T. Ohman, S. Soderholm, P. Hintsanen, E. Valimaki, N. Lietzen, C. MacKintosh, T. Aittokallio, S. Matikainen, and T. A. Nyman
MCP 13, 2604-2617 (1 October 2014)

DHX15 Senses Double-Stranded RNA in Myeloid Dendritic Cells
H. Lu, N. Lu, L. Weng, B. Yuan, Y.-j. Liu, and Z. Zhang
J. Immunol. 193, 1364-1372 (1 August 2014)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882