Essential Role of Rnd1 in Innate Immunity During Viral and Bacterial Infections

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2022 Jun 2

PMID 35654795

Authors

Akhilesh Kumar

Shalabh Mishra

Ashish Kumar

Ashwin Ashok Raut

Seiichi Sato

Akinori Takaoka

Himanshu Kumar

Affiliations

Soon will be listed here.

Abstract

Intracellular and cell surface pattern-recognition receptors (PRRs) are an essential part of innate immune recognition and host defense. Here, we have compared the innate immune responses between humans and bats to identify a novel membrane-associated protein, Rnd1, which defends against viral and bacterial infection in an interferon-independent manner. Rnd1 belongs to the Rho GTPase family, but unlike other small GTPase members, it is constitutively active. We show that Rnd1 is induced by pro-inflammatory cytokines during viral and bacterial infections and provides protection against these pathogens through two distinct mechanisms. Rnd1 counteracts intracellular calcium fluctuations by inhibiting RhoA activation, thereby inhibiting virus internalisation. On the other hand, Rnd1 also facilitates pro-inflammatory cytokines IL-6 and TNF-α through Plxnb1, which are highly effective against intracellular bacterial infections. These data provide a novel Rnd1-mediated innate defense against viral and bacterial infections.

Citing Articles

Gene expression profiles in respiratory settings in rats under extracorporeal membrane oxygenation.

Mori S, Ohtsuka T, Hashimoto K, Fujii Y, Harada E, Shigemori R J Thorac Dis. 2025; 17(1):31-41.

PMID: 39975719 PMC: 11833566. DOI: 10.21037/jtd-24-1661.

Boosting Clear Cell Renal Carcinoma-Specific Drug Discovery Using a Deep Learning Algorithm and Single-Cell Analysis.

Wang Y, Chen X, Tang N, Guo M, Ai D Int J Mol Sci. 2024; 25(7).

PMID: 38612943 PMC: 11012314. DOI: 10.3390/ijms25074134.

References

Ingle H, Kumar S, Raut A, Mishra A, Kulkarni D, Kameyama T . The microRNA miR-485 targets host and influenza virus transcripts to regulate antiviral immunity and restrict viral replication. Sci Signal. 2015; 8(406):ra126. DOI: 10.1126/scisignal.aab3183. View

Yoshida Y, Ogata A, Kang S, Ebina K, Shi K, Nojima S . Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications. Arthritis Rheumatol. 2015; 67(6):1481-90. PMC: 5032998. DOI: 10.1002/art.39086. View

Glennon N, Jabado O, Lo M, Shaw M . Transcriptome Profiling of the Virus-Induced Innate Immune Response in Pteropus vampyrus and Its Attenuation by Nipah Virus Interferon Antagonist Functions. J Virol. 2015; 89(15):7550-66. PMC: 4505658. DOI: 10.1128/JVI.00302-15. View

Streicker D, Gilbert A . Contextualizing bats as viral reservoirs. Science. 2020; 370(6513):172-173. DOI: 10.1126/science.abd4559. View

Banerjee A, Baker M, Kulcsar K, Misra V, Plowright R, Mossman K . Novel Insights Into Immune Systems of Bats. Front Immunol. 2020; 11:26. PMC: 7025585. DOI: 10.3389/fimmu.2020.00026. View

Portnoy D, Auerbuch V, Glomski I . The cell biology of Listeria monocytogenes infection: the intersection of bacterial pathogenesis and cell-mediated immunity. J Cell Biol. 2002; 158(3):409-14. PMC: 2173830. DOI: 10.1083/jcb.200205009. View

Calisher C, Childs J, Field H, Holmes K, Schountz T . Bats: important reservoir hosts of emerging viruses. Clin Microbiol Rev. 2006; 19(3):531-45. PMC: 1539106. DOI: 10.1128/CMR.00017-06. View

Wylie T, Garg R, Ridley A, Conte M . Analysis of the interaction of Plexin-B1 and Plexin-B2 with Rnd family proteins. PLoS One. 2017; 12(10):e0185899. PMC: 5645086. DOI: 10.1371/journal.pone.0185899. View

Allocati N, Petrucci A, Di Giovanni P, Masulli M, Di Ilio C, De Laurenzi V . Bat-man disease transmission: zoonotic pathogens from wildlife reservoirs to human populations. Cell Death Discov. 2016; 2:16048. PMC: 4979447. DOI: 10.1038/cddiscovery.2016.48. View

10.

Wennerberg K, Forget M, Ellerbroek S, Arthur W, Burridge K, Settleman J . Rnd proteins function as RhoA antagonists by activating p190 RhoGAP. Curr Biol. 2003; 13(13):1106-15. PMC: 6918695. DOI: 10.1016/s0960-9822(03)00418-4. View

11.

Mouly L, Gilhodes J, Lemarie A, Cohen-Jonathan Moyal E, Toulas C, Favre G . The RND1 Small GTPase: Main Functions and Emerging Role in Oncogenesis. Int J Mol Sci. 2019; 20(15). PMC: 6696182. DOI: 10.3390/ijms20153612. View

12.

Fujioka Y, Tsuda M, Nanbo A, Hattori T, Sasaki J, Sasaki T . A Ca(2+)-dependent signalling circuit regulates influenza A virus internalization and infection. Nat Commun. 2014; 4:2763. DOI: 10.1038/ncomms3763. View

13.

Oinuma I, Katoh H, Negishi M . Molecular dissection of the semaphorin 4D receptor plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons. J Neurosci. 2004; 24(50):11473-80. PMC: 6730355. DOI: 10.1523/JNEUROSCI.3257-04.2004. View

14.

White R, Razgour O . Emerging zoonotic diseases originating in mammals: a systematic review of effects of anthropogenic land-use change. Mamm Rev. 2020; 50(4):336-352. PMC: 7300897. DOI: 10.1111/mam.12201. View

15.

Zhou P, Tachedjian M, Wynne J, Boyd V, Cui J, Smith I . Contraction of the type I IFN locus and unusual constitutive expression of IFN-α in bats. Proc Natl Acad Sci U S A. 2016; 113(10):2696-701. PMC: 4790985. DOI: 10.1073/pnas.1518240113. View

16.

Barberis D, Casazza A, Sordella R, Corso S, Artigiani S, Settleman J . p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling. J Cell Sci. 2005; 118(Pt 20):4689-700. DOI: 10.1242/jcs.02590. View

17.

Afgan E, Baker D, Batut B, van den Beek M, Bouvier D, cech M . The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update. Nucleic Acids Res. 2018; 46(W1):W537-W544. PMC: 6030816. DOI: 10.1093/nar/gky379. View

18.

Chapoval S . Neuroimmune semaphorins as costimulatory molecules and beyond. Mol Med. 2018; 24(1):13. PMC: 6016892. DOI: 10.1186/s10020-018-0014-9. View

19.

Hare D, Collins S, Mukherjee S, Loo Y, Gale Jr M, Janssen L . Membrane Perturbation-Associated Ca2+ Signaling and Incoming Genome Sensing Are Required for the Host Response to Low-Level Enveloped Virus Particle Entry. J Virol. 2016; 90(6):3018-27. PMC: 4810640. DOI: 10.1128/JVI.02642-15. View

20.

Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley D . Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc. 2012; 7(3):562-78. PMC: 3334321. DOI: 10.1038/nprot.2012.016. View