Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling.
The oligoadenylate synthetase (OAS) enzymes are cytoplasmic dsRNA sensors belonging to the antiviral innate immune system. Upon binding to viral dsRNA, the OAS enzymes synthesize 2'-5' linked oligoadenylates (2-5As) that initiate an RNA decay pathway to impair viral replication. The human OAS-like (OASL) protein, however, does not harbor the catalytic activity required for synthesizing 2-5As and differs from the other human OAS family members by having two C-terminal ubiquitin-like domains. In spite of its lack of enzymatic activity, human OASL possesses antiviral activity. It was recently demonstrated that the ubiquitin-like domains of OASL could substitute for K63-linked poly-ubiquitin and interact with the CARDs of RIG-I and thereby enhance RIG-I signaling. However, the role of the OAS-like domain of OASL remains unclear. Here we present the crystal structure of the OAS-like domain, which shows a striking similarity with activated OAS1. Furthermore, the structure of the OAS-like domain shows that OASL has a dsRNA binding groove. We demonstrate that the OAS-like domain can bind dsRNA and that mutating key residues in the dsRNA binding site is detrimental to the RIG-I signaling enhancement. Hence, binding to dsRNA is an important feature of OASL that is required for enhancing RIG-I signaling.
Centre for Structural Biology, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
Mikkel Søes
MS
Ibsen
Centre for Structural Biology, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
Hans Henrik
HH
Gad
Centre for Structural Biology, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
Line Lykke
LL
Andersen
Institute of Molecular Medicine, University Hospital, University of Bonn, Bonn 53127, Germany.
Veit
V
Hornung
Department of Virology, University of Turku, 20520 Turku, Finland Viral Infections Unit, National Institute for Health and Welfare, 00300 Helsinki, Finland.
Ilkka
I
Julkunen
Department of Microbiology and Molecular Genetics, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Saumendra N
SN
Sarkar
Centre for Structural Biology, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark rh@mbg.au.dk.
Rune
R
Hartmann
D015088:2',5'-Oligoadenylate Synthetase / Q000737:chemistry* / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D055503:Protein Multimerization; D012330:RNA, Double-Stranded / Q000737:chemistry* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction
D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; C115020:OASL protein, human; D015088:2',5'-Oligoadenylate Synthetase; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases