The RNA Helicase DDX3X is an Essential Mediator of Innate Antimicrobial Immunity

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2018 Nov 27

PMID 30475900

Citations 41

Authors

Daniel Szappanos

Roland Tschismarov

Thomas Perlot

Sandra Westermayer

Katrin Fischer

Ekaterini Platanitis

Fabian Kallinger

Maria Novatchkova

Caroline Lassnig

Mathias Muller

Veronika Sexl

Keiryn L Bennett

Michelle Foong-Sobis

Josef M Penninger

Thomas Decker

Affiliations

Soon will be listed here.

Abstract

DExD/H box RNA helicases, such as the RIG-I-like receptors (RLR), are important components of the innate immune system. Here we demonstrate a pivotal and sex-specific role for the heterosomal isoforms of the DEAD box RNA helicase DDX3 in the immune system. Mice lacking DDX3X during hematopoiesis showed an altered leukocyte composition in bone marrow and spleen and a striking inability to combat infection with Listeria monocytogenes. Alterations in innate immune responses resulted from decreased effector cell availability and function as well as a sex-dependent impairment of cytokine synthesis. Thus, our data provide further in vivo evidence for an essential contribution of a non-RLR DExD/H RNA helicase to innate immunity and suggest it may contribute to sex-related differences in resistance to microbes and resilience to inflammatory disease.

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References

Soulat D, Burckstummer T, Westermayer S, Goncalves A, Bauch A, Stefanovic A . The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. EMBO J. 2008; 27(15):2135-46. PMC: 2453059. DOI: 10.1038/emboj.2008.126. View

Stockinger S, Kastner R, Kernbauer E, Pilz A, Westermayer S, Reutterer B . Characterization of the interferon-producing cell in mice infected with Listeria monocytogenes. PLoS Pathog. 2009; 5(3):e1000355. PMC: 2654726. DOI: 10.1371/journal.ppat.1000355. View

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

Bol G, Xie M, Raman V . DDX3, a potential target for cancer treatment. Mol Cancer. 2015; 14:188. PMC: 4636063. DOI: 10.1186/s12943-015-0461-7. View

Hansen K, Prabakaran T, Laustsen A, Jorgensen S, Rahbaek S, Jensen S . Listeria monocytogenes induces IFNβ expression through an IFI16-, cGAS- and STING-dependent pathway. EMBO J. 2014; 33(15):1654-66. PMC: 4194099. DOI: 10.15252/embj.201488029. View

Clark S, Filak H, Guthrie B, Schmidt R, Jamieson A, Merkel P . Bacterial Manipulation of NK Cell Regulatory Activity Increases Susceptibility to Listeria monocytogenes Infection. PLoS Pathog. 2016; 12(6):e1005708. PMC: 4905663. DOI: 10.1371/journal.ppat.1005708. View

Carrero J, Calderon B, Unanue E . Type I interferon sensitizes lymphocytes to apoptosis and reduces resistance to Listeria infection. J Exp Med. 2004; 200(4):535-40. PMC: 2211931. DOI: 10.1084/jem.20040769. View

Berg R, Cordes C, Forman J . Contribution of CD8+ T cells to innate immunity: IFN-gamma secretion induced by IL-12 and IL-18. Eur J Immunol. 2002; 32(10):2807-16. DOI: 10.1002/1521-4141(2002010)32:10<2807::AID-IMMU2807>3.0.CO;2-0. View

Valiente-Echeverria F, Hermoso M, Soto-Rifo R . RNA helicase DDX3: at the crossroad of viral replication and antiviral immunity. Rev Med Virol. 2015; 25(5):286-99. DOI: 10.1002/rmv.1845. View

10.

Kernbauer E, Maier V, Stoiber D, Strobl B, Schneckenleithner C, Sexl V . Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection. PLoS Pathog. 2012; 8(6):e1002763. PMC: 3375314. DOI: 10.1371/journal.ppat.1002763. View

11.

Linder P, Jankowsky E . From unwinding to clamping - the DEAD box RNA helicase family. Nat Rev Mol Cell Biol. 2011; 12(8):505-16. DOI: 10.1038/nrm3154. View

12.

Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R . Immune response in mice that lack the interferon-gamma receptor. Science. 1993; 259(5102):1742-5. DOI: 10.1126/science.8456301. View

13.

Tripp C, Gately M, Hakimi J, Ling P, UNANUE E . Neutralization of IL-12 decreases resistance to Listeria in SCID and C.B-17 mice. Reversal by IFN-gamma. J Immunol. 1994; 152(4):1883-7. View

14.

Fairman-Williams M, Guenther U, Jankowsky E . SF1 and SF2 helicases: family matters. Curr Opin Struct Biol. 2010; 20(3):313-24. PMC: 2916977. DOI: 10.1016/j.sbi.2010.03.011. View

15.

Wu X, Dao Thi V, Huang Y, Billerbeck E, Saha D, Hoffmann H . Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell. 2017; 172(3):423-438.e25. PMC: 5786493. DOI: 10.1016/j.cell.2017.11.018. View

16.

Andersson A, Dai W, Di Santo J, Brombacher F . Early IFN-gamma production and innate immunity during Listeria monocytogenes infection in the absence of NK cells. J Immunol. 1998; 161(10):5600-6. View

17.

Li Q, Brass A, Ng A, Hu Z, Xavier R, Liang T . A genome-wide genetic screen for host factors required for hepatitis C virus propagation. Proc Natl Acad Sci U S A. 2009; 106(38):16410-5. PMC: 2752535. DOI: 10.1073/pnas.0907439106. View

18.

Fullam A, Schroder M . DExD/H-box RNA helicases as mediators of anti-viral innate immunity and essential host factors for viral replication. Biochim Biophys Acta. 2013; 1829(8):854-65. PMC: 7157912. DOI: 10.1016/j.bbagrm.2013.03.012. View

19.

Auerbuch V, Brockstedt D, Meyer-Morse N, ORiordan M, Portnoy D . Mice lacking the type I interferon receptor are resistant to Listeria monocytogenes. J Exp Med. 2004; 200(4):527-33. PMC: 2211930. DOI: 10.1084/jem.20040976. View

20.

Sekiguchi T, Iida H, Fukumura J, Nishimoto T . Human DDX3Y, the Y-encoded isoform of RNA helicase DDX3, rescues a hamster temperature-sensitive ET24 mutant cell line with a DDX3X mutation. Exp Cell Res. 2004; 300(1):213-22. DOI: 10.1016/j.yexcr.2004.07.005. View