The DEAH-box RNA helicase DHX15 activates NF-κB and MAPK signaling downstream of MAVS during antiviral responses.
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.
1Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Kenta
K
Mosallanejad
Yusuke
Y
Sekine
Seiko
S
Ishikura-Kinoshita
Kazuo
K
Kumagai
Tetsuo
T
Nagano
Atsushi
A
Matsuzawa
Kohsuke
K
Takeda
Isao
I
Naguro
Hidenori
H
Ichijo
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D004686:Encephalomyocarditis virus / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D011070:Poly I-C / Q000235:genetics; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D015850:Interleukin-6; C505371:MAVS protein, human; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D048031:JNK Mitogen-Activated Protein Kinases; C539469:DHX15 protein, human; D020365:RNA Helicases; D011070:Poly I-C