ABSTRACT In the past two decades, emerging studies have suggested that DExD/H box helicases belonging to helicase superfamily 2 (SF2) play essential roles in antiviral innate immunity.

However, the antiviral functions of helicase SF1, which shares a conserved helicase core with SF2, are little understood. Here we demonstrate that zinc finger NFX1-type containing 1 (ZNFX1),

a helicase SF1, is an interferon (IFN)-stimulated, mitochondrial-localised dsRNA sensor that specifically restricts the replication of RNA viruses. Upon virus infection, ZNFX1 immediately

recognizes viral RNA through its Armadillo-type fold and P-loop domain and then interacts with mitochondrial antiviral signalling protein to initiate the type I IFN response without

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OTHERS _N_6-METHYLADENOSINE RNA MODIFICATION SUPPRESSES ANTIVIRAL INNATE SENSING PATHWAYS VIA RESHAPING DOUBLE-STRANDED RNA Article Open access 11 March 2021 IFI16 DIRECTLY SENSES VIRAL RNA

AND ENHANCES RIG-I TRANSCRIPTION AND ACTIVATION TO RESTRICT INFLUENZA VIRUS INFECTION Article 13 May 2021 PWWP3A DISRUPTS THE ASSEMBLY OF VISA/MAVS SIGNALOSOME TO INHIBIT INNATE IMMUNE

RESPONSE AGAINST RNA VIRUSES Article Open access 01 May 2025 DATA AVAILABILITY RNA sequencing data that support the findings of this study have been deposited in the Gene Expression Omnibus

(GEO) under accession code GSE132979. Source data for Figs. 1–7 and Extended Data Figs. 1–7 have been provided as Statistics Source Data. All other data supporting the findings of this study

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Central  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by the National Natural Science Foundation (NNSF) of China under grants 31770943, 81430099 and 31900661

and by the Natural Science Foundation of Guangdong Province of China under grants 2015A030306043, 2018A030313924 and 2018A030313051. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * State Key

Laboratory of Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, School of Life Science, Sun Yat-sen University, Guangzhou, China Yao Wang, Shaochun Yuan, Xin

Jia, Yong Ge, Tao Ling, Meng Nie, Xihong Lan, Shangwu Chen & Anlong Xu * School of Life Science, Beijing University of Chinese Medicine, Beijing, China Anlong Xu Authors * Yao Wang View

author publications You can also search for this author inPubMed Google Scholar * Shaochun Yuan View author publications You can also search for this author inPubMed Google Scholar * Xin Jia

View author publications You can also search for this author inPubMed Google Scholar * Yong Ge View author publications You can also search for this author inPubMed Google Scholar * Tao

Ling View author publications You can also search for this author inPubMed Google Scholar * Meng Nie View author publications You can also search for this author inPubMed Google Scholar *

Xihong Lan View author publications You can also search for this author inPubMed Google Scholar * Shangwu Chen View author publications You can also search for this author inPubMed Google

Scholar * Anlong Xu View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Y.W., S.Y. and A.X. conceived the ideas and designed the experiments.

Y.W., X.J., Y.G., T.L., M.N. and X.L. performed the experiments. Y.W., S.Y. and X.J. analysed the data. S.Y., Y.W., X.J. and S.C. contributed to editing the manuscript. S.Y. and A.X.

supervised the research and wrote the paper. S.Y. and X.J. are joint co first authors. CORRESPONDING AUTHOR Correspondence to Anlong Xu. ETHICS DECLARATIONS COMPETING INTERESTS The authors

declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

EXTENDED DATA EXTENDED DATA FIG. 1 BIOINFORMATICS ANALYSIS OF IN VITRO TRANSCRIPTION-SEQUENCING APA SITES (IVT-SAPAS) DATA OF VSV-INFECTED MACROPHAGES AND PREVIOUSLY COLLECTED VIRAL

INFECTION MICROARRAY DATA. A, IVT-SAPAS revealed the genes with transcriptional changes in MDMs infected with VSV for 0, 2, 4, 8, 16, 24 hrs. B-C, The percentage of GFP+ cells of FACS

analysis of A549 cells transfected with control siRNA or the indicated siRNAs followed by VSV-eGFP infection for another 6 hrs (n = 3 independent experiments). D, qRT-PCR revealed the mRNA

expression of target gene in A549 cells transfected with indicated siRNAs for 48 hrs (n = 3 independent experiments). E-F, RNA levels of Znfx1 and Rig-I are significantly increased after

different virial infection in different cell types. G, Schematic representation of ZNFX1 promoter containing core region bound by STAT1, STAT2, IRF1 and IRF9. For E, n = 3 independent

experiments. Data in F, n = 4 wells for SeV infected epithelial cells and n = 6 wells for uninfected cells; n = 5 samples for IVA infected pDCs; n = 4 independent experiments for SeV

infected monocytoid cells; n = 2 independent experiments for SeV or HIV infected Macrophages or mDCs. All data are shown as the mean ± s.d. Statistical differences were detected using

two-tailed unpaired Student’s t-tests. Source data EXTENDED DATA FIG. 2 ZNFX1 DEFICIENCY IMPAIRS ANTIVIRAL IMMUNE RESPONSE _IN VITRO_ AND _IN VIVO_. A, Quantitative RT-PCR (qRT-PCR) analysis

of _Znfx1_ mRNA expression in A549 and L929 cells transfected with control siRNA or ZNFX1 siRNA 1#, 2# or 3# for 48 hrs (n = 3 independent experiments). B, Western blot analysis of ZNFX1

protein expression in A549 cells transfected with control siRNA or human ZNFX1 siRNA 1# for 48 hrs. C, ELISA of IFN-α or IFN-β production in cell supernatants from A549 cells with target

gene knockdown for 48 hrs followed by VSV infection or poly I:C stimulation for another 12 hrs (n = 4 independent experiments). D, qRT-PCR analysis of VSV mRNA expression (left panel) and

plaque assay analysis of VSV titer (right panel) of A549 cells transfected with RIG-I, ZNFX1 expressing plasmids or empty vector plasmid for 24 hrs and then infected with VSV at an MOI of 2

for 16 hrs (n = 3 independent experiments). E, FACS analysis of _Znfx1_+/+ and _Znfx1_-/- 293T cells followed by VSV-eGFP infection at 0.5 MOI for the indicated time points (n = 3

independent experiments). F, _Znfx1_-/- 293T and A549 clones were generated by the CRISPR-Cas9 method. Deficiency of target genes in the KO clones were confirmed by immunoblotting analysis.

G, qRT-PCR analysis of viral mRNA transcripts in VSV, EMCV, H1N1 and HSV-1 infected A549 cells with control siRNA (si Control) or _Znfx1_-specific siRNA (si ZNFX1) (n = 3 independent

experiments). H, ELISA of IFN-α in supernatants of BMDMs from WT and _Znfx1_-/- mice infected with VSV or HSV-1 for 16 hrs (n = 5 independent experiments). All data are shown as the mean ± 

s.d. P values were calculated using two-tailed unpaired Student’s t-test. For B, F, the experiments were repeated three times, independently, with similar results obtained. Source data

Source data EXTENDED DATA FIG. 3 ZNFX1 POSITIVELY REGULATES IFN-Β SIGNALING. A, Illustration of the CRISPR-Cas9 strategy to generate _Znfx1_-deficient mice and primer design used in (B). B,

Genotyping of the ZNFX1 mutant pups. C, Immunoblot analysis of ZNFX1 protein levels in _Znfx1_+/+ and _Znfx1_-/- MEFs cells. D, qRT-PCR analysis of _Ifnb1_ and ISGs mRNA levels in A549 cells

transfected with siControl (si Ctrl) or si ZNFX1 for 48 hrs and then infected with VSV for the indicated time points (n = 3 independent experiments). E, qRT-PCR analysis of _Ifnb1_ and ISGs

mRNA expression in _Znfx1_+/+ and _Znfx1_-/- 293T cells followed by VSV infected with increasing MOI (0.5 and 1) for 0, 8 and 16 hrs (n = 3 independent experiments). For B, C, the

experiments were repeated three times, independently, with similar results obtained. Data in D, E are the mean ± s.d. P values were calculated using two-tailed unpaired Student’s t-test.

Source data Source data EXTENDED DATA FIG. 4 ZNFX1 LOCALIZES TO MITOCHONDRIA AND INTERACTS WITH MAVS. A, FACS analysis of _Znfx1_-/- A549 cells transfected with ZNFX1 and its mutants

expressing plasmids or empty vector (EV) for 24 hrs followed by VSV-eGFP infection at an MOI of 2 for 6 hrs. B, Endogenous level of ZNFX1 protein in mitochondrial fractions in WT and

_Mavs_-/- 293T with or without VSV infection at 1 MOI for 6 hrs. COX-IV was used as the loading control. Data are representative of at least three independent experiments. Source data

EXTENDED DATA FIG. 5 THE EXPRESSION OF _ZNFX1_ IN DIFFERENT TISSUES AND CELL TYPES, AND THE PHYLOGENETIC TREE OF _ZNFX1_. A-C, The expression of _Znfx1, Rig-I and Mda5_ in different tissues

and cell types as per BioGPS. D, Phylogenetic tree of ZNFX1 and RIG-I using an amino acid sequence alignment among different species. EXTENDED DATA FIG. 6 ALIGNMENT OF ZNFX1 AMINO ACID

SEQUENCES IN HUMAN, MOUSE, RAT AND ZEBRAFISH. Shading indicates sequence conservation, with darker gray indicating a higher degree of conservation. EXTENDED DATA FIG. 7 WORK MODEL OF

MITOCHONDRIA-LOCALIZED ZNFX1 FUNCTIONS AS A DSRNA SENSOR TO INITIATE ANTIVIRAL RESPONSES THROUGH MAVS. Upon RNA virus infection, ZNFX1 induces type I interferon response by interacting with

MAVS in the early stage, thus primes the expression of a number of ISGs, including RIG-I and MDA5. The induced sensors further enhance the antiviral immune response by amplifying ISGs

expression. SUPPLEMENTARY INFORMATION REPORTING SUMMARY SUPPLEMENTARY TABLES 1 Conservative analysis of ZNFX1 and DDX58 in different species. SUPPLEMENTARY TABLES 2 Information about the

primers used in the study. SOURCE DATA SOURCE DATA FIG. 1 Statistical Source Data SOURCE DATA FIG. 1 Unprocessed Western blots and/or gels SOURCE DATA FIG. 2 Statistical Source Data SOURCE

DATA FIG. 2 Unprocessed Western blots and/or gels SOURCE DATA FIG. 3 Statistical Source Data SOURCE DATA FIG. 4 Statistical Source Data SOURCE DATA FIG. 4 Unprocessed Western blots and/or

gels SOURCE DATA FIG. 5 Statistical Source Data SOURCE DATA FIG. 5 Unprocessed Western blots and/or gels SOURCE DATA FIG. 6 Statistical Source Data SOURCE DATA FIG. 6 Unprocessed Western

blots and/or gels SOURCE DATA FIG. 7 Statistical Source Data SOURCE DATA EXTENDED DATA FIG. 1 Statistical Source Data SOURCE DATA EXTENDED DATA FIG. 2 Statistical Source Data SOURCE DATA

EXTENDED DATA FIG. 2 Unprocessed Western blots and/or gels SOURCE EXTENDED DATA FIG. 3 Statistical Source Data SOURCE DATA EXTENDED DATA FIG. 3 Unprocessed Western blots and/or gels SOURCE

DATA EXTENDED DATA FIG. 4 Unprocessed Western blots and/or gels RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wang, Y., Yuan, S., Jia, X. _et al._

Mitochondria-localised ZNFX1 functions as a dsRNA sensor to initiate antiviral responses through MAVS. _Nat Cell Biol_ 21, 1346–1356 (2019). https://doi.org/10.1038/s41556-019-0416-0

Download citation * Received: 16 October 2018 * Accepted: 26 September 2019 * Published: 04 November 2019 * Issue Date: November 2019 * DOI: https://doi.org/10.1038/s41556-019-0416-0 SHARE

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