Initiation of a ZAKα-dependent ribotoxic stress response by the innate immunity endoribonuclease RNase L
Jiajia Xi,
Goda Snieckute,
José Francisco Martínez,
Frederic Schrøder Wenzel Arendrup,
Abhishek Asthana,
Christina Gaughan,
Anders H. Lund,
Simon Bekker-Jensen,
Robert H. Silverman
Affiliations
Jiajia Xi
Department Cancer Biology, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, OH 44195, USA; Corresponding author
Goda Snieckute
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; Center for Gene Expression, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
José Francisco Martínez
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; Center for Gene Expression, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
Frederic Schrøder Wenzel Arendrup
Biotech Research and Innovation Center, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark
Abhishek Asthana
Department Cancer Biology, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, OH 44195, USA
Christina Gaughan
Department Cancer Biology, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, OH 44195, USA
Anders H. Lund
Biotech Research and Innovation Center, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark
Simon Bekker-Jensen
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; Center for Gene Expression, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark; Corresponding author
Robert H. Silverman
Department Cancer Biology, Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, OH 44195, USA; Corresponding author
Summary: RNase L is an endoribonuclease of higher vertebrates that functions in antiviral innate immunity. Interferons induce oligoadenylate synthetase enzymes that sense double-stranded RNA of viral origin leading to the synthesis of 2′,5′-oligoadenylate (2-5A) activators of RNase L. However, it is unknown precisely how RNase L remodels the host cell transcriptome. To isolate effects of RNase L from other effects of double-stranded RNA or virus, 2-5A is directly introduced into cells. Here, we report that RNase L activation by 2-5A causes a ribotoxic stress response involving the MAP kinase kinase kinase (MAP3K) ZAKα, MAP2Ks, and the stress-activated protein kinases JNK and p38α. RNase L activation profoundly alters the transcriptome by widespread depletion of mRNAs associated with different cellular functions but also by JNK/p38α-stimulated induction of inflammatory genes. These results show that the 2-5A/RNase L system triggers a protein kinase cascade leading to proinflammatory signaling and apoptosis.
