TY  - JOUR
AU  - Merold, Veronika
AU  - Bekere, Indra
AU  - Kretschmer, Stefanie
AU  - Schnell, Adrian F
AU  - Kmiec, Dorota
AU  - Sivarajan, Rinu
AU  - Lammens, Katja
AU  - Liu, Rou
AU  - Mergner, Julia
AU  - Teppert, Julia
AU  - Hirschenberger, Maximilian
AU  - Henrici, Alexander
AU  - Hammes, Sarah
AU  - Buder, Kathrin
AU  - Weitz, Marcus
AU  - Hackmann, Karl
AU  - Koenig, Lars M
AU  - Pichlmair, Andreas
AU  - Schwierz, Nadine
AU  - Sparrer, Konstantin M J
AU  - Lee-Kirsch, Min Ae
AU  - de Oliveira Mann, Carina C
TI  - Structural basis for OAS2 regulation and its antiviral function.
JO  - Molecular cell
VL  - 85
IS  - 11
SN  - 1097-2765
CY  - [Cambridge, Mass.]
PB  - Cell Press
M1  - DZNE-2025-00674
SP  - 2176 - 2193.e13
PY  - 2025
AB  - Oligoadenylate synthetase (OAS) proteins are immune sensors for double-stranded RNA and are critical for restricting viruses. OAS2 comprises two OAS domains, only one of which can synthesize 2'-5'-oligoadenylates for RNase L activation. Existing structures of OAS1 provide a model for enzyme activation, but they do not explain how multiple OAS domains discriminate RNA length. Here, we discover that human OAS2 exists in an auto-inhibited state as a zinc-mediated dimer and present a mechanism for RNA length discrimination: the catalytically deficient domain acts as a molecular ruler that prevents autoreactivity to short RNAs. We demonstrate that dimerization and myristoylation localize OAS2 to Golgi membranes and that this is required for OAS2 activation and the restriction of viruses that exploit the endomembrane system for replication, e.g., coronaviruses. Finally, our results highlight the non-redundant role of OAS proteins and emphasize the clinical relevance of OAS2 by identifying a patient with a loss-of-function mutation associated with autoimmune disease.
KW  - 2',5'-Oligoadenylate Synthetase: genetics
KW  - 2',5'-Oligoadenylate Synthetase: chemistry
KW  - 2',5'-Oligoadenylate Synthetase: metabolism
KW  - Humans
KW  - Golgi Apparatus: enzymology
KW  - Golgi Apparatus: virology
KW  - Protein Multimerization
KW  - HEK293 Cells
KW  - Virus Replication
KW  - Mutation
KW  - RNA, Double-Stranded: metabolism
KW  - RNA, Double-Stranded: genetics
KW  - HeLa Cells
KW  - Endoribonucleases: metabolism
KW  - Endoribonucleases: genetics
KW  - Structure-Activity Relationship
KW  - Adenine Nucleotides
KW  - Oligoribonucleotides
KW  - OAS2 (Other)
KW  - RNA sensing (Other)
KW  - RNase L (Other)
KW  - innate immunity (Other)
KW  - localization (Other)
KW  - oligoadenylates (Other)
KW  - structural biology (Other)
KW  - virus restriction (Other)
KW  - 2',5'-Oligoadenylate Synthetase (NLM Chemicals)
KW  - OAS2 protein, human (NLM Chemicals)
KW  - 2',5'-oligoadenylate (NLM Chemicals)
KW  - RNA, Double-Stranded (NLM Chemicals)
KW  - 2-5A-dependent ribonuclease (NLM Chemicals)
KW  - Endoribonucleases (NLM Chemicals)
KW  - Adenine Nucleotides (NLM Chemicals)
KW  - Oligoribonucleotides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40412389
DO  - DOI:10.1016/j.molcel.2025.05.001
UR  - https://pub.dzne.de/record/279044
ER  -