PUBLICATION

Opposing effects of deubiquitinase OTUD3 in innate immunity against RNA and DNA viruses

Authors

Cai, X., Zhou, Z., Zhu, J., Liu, X., Ouyang, G., Wang, J., Li, Z., Li, X., Zha, H., Zhu, C., Rong, F., Tang, J., Liao, Q., Chen, X., Xiao, W.

ID

ZDB-PUB-220609-5

Date

2022

Source

Cell Reports 39: 110920 (Journal)

Registered Authors

Li, Zhi, Ouyang, Gang, Rong, Fangjing, Xiao, Wuhan

Keywords

CP: Immunology, CP: Molecular biology, MDA5, OTUD3, RIG-I, cGAS, deubiquitination, innate immunity

MeSH Terms

Mice
Nucleotidyltransferases
Zebrafish*/metabolism
Animals
Deubiquitinating Enzymes
RNA Viruses*
Interferon-Induced Helicase, IFIH1/metabolism
Immunity, Innate
DEAD Box Protein 58/metabolism
RNA, Viral/metabolism
DNA Viruses
Antiviral Agents

(all 12)

PubMed

35675783 Full text @ Cell Rep.

Abstract

Retinoic acid-inducible-I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and cyclic GMP-AMP synthase (cGAS) genes encode essential cytosolic receptors mediating antiviral immunity against viruses. Here, we show that OTUD3 has opposing role in response to RNA and DNA virus infection by removing distinct types of RIG-I/MDA5 and cGAS polyubiquitination. OTUD3 binds to RIG-I and MDA5 and removes K63-linked ubiquitination. This serves to reduce the binding of RIG-I and MDA5 to viral RNA and the downstream adaptor MAVS, leading to the suppression of the RNA virus-triggered innate antiviral responses. Meanwhile, OTUD3 associates with cGAS and targets at Lys279 to deubiquitinate K48-linked ubiquitination, resulting in the enhancement of cGAS protein stability and DNA-binding ability. As a result, Otud3-deficient mice and zebrafish are more resistant to RNA virus infection but are more susceptible to DNA virus infection. These findings demonstrate that OTUD3 limits RNA virus-triggered innate immunity but promotes DNA virus-triggered innate immunity.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	viral treatment by exposure to environment: Viruses	Protruding-mouth	whole organism ifnphi1 expression increased amount, abnormal	Fig. S7
AB	viral treatment by exposure to environment: Viruses	Protruding-mouth	whole organism pkz expression increased amount, abnormal	Fig. S7
AB	viral treatment by exposure to environment: Viruses	Protruding-mouth	whole organism decreased life span, abnormal	Fig. S9
AB	viral treatment by exposure to environment: Sprivivirus cyprinus	Protruding-mouth	whole organism ifnphi1 expression increased amount, abnormal	Fig. S7
AB	viral treatment by exposure to environment: Sprivivirus cyprinus	Protruding-mouth	whole organism pkz expression increased amount, abnormal	Fig. S7
AB	viral treatment by exposure to environment: Sprivivirus cyprinus	Protruding-mouth	whole organism decreased life span, abnormal	Fig. S7
AB	viral treatment by injection: Sprivivirus cyprinus	Days 45-89	liver has extra parts of type liver vacuole, abnormal	Fig. S7
AB	viral treatment by injection: Sprivivirus cyprinus	Days 45-89	trunk hemorrhagic, abnormal	Fig. S7
AB	viral treatment by injection: Sprivivirus cyprinus	Days 45-89	trunk swollen, abnormal	Fig. S7
otud3^{ihb20201006/ihb20201006} (AB)	viral treatment by exposure to environment: Viruses	Protruding-mouth	defense response to virus decreased process quality, abnormal	Fig. S9

1 - 10 of 20

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ihb20201006		Small Deletion	otud3

Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
AB
otud3^{ihb20201006/ihb20201006} (AB)

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Cai et al., 2022 ZDB-PUB-220609-5 PMID:35675783

Opposing effects of deubiquitinase OTUD3 in innate immunity against RNA and DNA viruses

Cai et al., 2022

ZDB-PUB-220609-5
PMID:35675783