Cargando…
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 (...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446440/ https://www.ncbi.nlm.nih.gov/pubmed/25925578 http://dx.doi.org/10.1093/nar/gkv389 |
_version_ | 1782373425294082048 |
---|---|
author | Ibsen, Mikkel Søes Gad, Hans Henrik Andersen, Line Lykke Hornung, Veit Julkunen, Ilkka Sarkar, Saumendra N. Hartmann, Rune |
author_facet | Ibsen, Mikkel Søes Gad, Hans Henrik Andersen, Line Lykke Hornung, Veit Julkunen, Ilkka Sarkar, Saumendra N. Hartmann, Rune |
author_sort | Ibsen, Mikkel Søes |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4446440 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-44464402015-06-15 Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling Ibsen, Mikkel Søes Gad, Hans Henrik Andersen, Line Lykke Hornung, Veit Julkunen, Ilkka Sarkar, Saumendra N. Hartmann, Rune Nucleic Acids Res Structural Biology 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. Oxford University Press 2015-05-26 2015-04-29 /pmc/articles/PMC4446440/ /pubmed/25925578 http://dx.doi.org/10.1093/nar/gkv389 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Structural Biology Ibsen, Mikkel Søes Gad, Hans Henrik Andersen, Line Lykke Hornung, Veit Julkunen, Ilkka Sarkar, Saumendra N. Hartmann, Rune Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling |
title | Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling |
title_full | Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling |
title_fullStr | Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling |
title_full_unstemmed | Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling |
title_short | Structural and functional analysis reveals that human OASL binds dsRNA to enhance RIG-I signaling |
title_sort | structural and functional analysis reveals that human oasl binds dsrna to enhance rig-i signaling |
topic | Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446440/ https://www.ncbi.nlm.nih.gov/pubmed/25925578 http://dx.doi.org/10.1093/nar/gkv389 |
work_keys_str_mv | AT ibsenmikkelsøes structuralandfunctionalanalysisrevealsthathumanoaslbindsdsrnatoenhancerigisignaling AT gadhanshenrik structuralandfunctionalanalysisrevealsthathumanoaslbindsdsrnatoenhancerigisignaling AT andersenlinelykke structuralandfunctionalanalysisrevealsthathumanoaslbindsdsrnatoenhancerigisignaling AT hornungveit structuralandfunctionalanalysisrevealsthathumanoaslbindsdsrnatoenhancerigisignaling AT julkunenilkka structuralandfunctionalanalysisrevealsthathumanoaslbindsdsrnatoenhancerigisignaling AT sarkarsaumendran structuralandfunctionalanalysisrevealsthathumanoaslbindsdsrnatoenhancerigisignaling AT hartmannrune structuralandfunctionalanalysisrevealsthathumanoaslbindsdsrnatoenhancerigisignaling |