scholarly journals Repeated MDA5 Gene Loss in Birds: An Evolutionary Perspective

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2131
Author(s):  
Veronika Krchlíková ◽  
Tomáš Hron ◽  
Martin Těšický ◽  
Tao Li ◽  
Jiří Hejnar ◽  
...  
Keyword(s):  
Negative Selection ◽  
Gene Loss ◽  
Evolutionary Perspective ◽  
Compensatory Evolution ◽  
Danger Signals ◽  
Downstream Signaling ◽  
Interferon Stimulated Genes ◽  
Avian Genome ◽  
I Gene ◽  
Inducible Gene

Two key cytosolic receptors belonging to the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family sense the viral RNA-derived danger signals: RIG-I and melanoma differentiation-associated protein 5 (MDA5). Their activation establishes an antiviral state by downstream signaling that ultimately activates interferon-stimulated genes (ISGs). While in rare cases RIG-I gene loss has been detected in mammalian and avian species, most notably in the chicken, MDA5 pseudogenization has only been detected once in mammals. We have screened over a hundred publicly available avian genome sequences and describe an independent disruption of MDA5 in two unrelated avian lineages, the storks (Ciconiiformes) and the rallids (Gruiformes). The results of our RELAX analysis confirmed the absence of negative selection in the MDA5 pseudogene. In contrast to our prediction, we have shown, using multiple dN/dS-based approaches, that the MDA5 loss does not appear to have resulted in any compensatory evolution in the RIG-I gene, which may partially share its ligand-binding specificity. Together, our results indicate that the MDA5 pseudogenization may have important functional effects on immune responsiveness in these two avian clades.

scholarly journals Modeling colicin operons as genetic arms in plasmid-genome conflicts

2021 ◽  
Author(s):  
Pavithra Anantharaman Sudhakari ◽  
Bhaskar Chandra Mohan Ramisetty
Keyword(s):  
Negative Selection ◽  
Bacterial Genome ◽  
Evolutionary Perspective ◽  
Bacterial Genomes ◽  
Sequence Analyses ◽  
Agent Based ◽  
Physiological Relevance ◽  
Maintenance Systems ◽  
Selection Of ◽  
Lethal Genes

Plasmids are acellular propagating entities that depend, as molecular parasites, on bacteria for propagation. The conflict between the bacterial genome and the parasitic plasmids allows the emergence of genetic arms such as Colicin (Col) operons. Endonuclease Col operons encode three proteins; an endonuclease colicin (cleaves nucleic acids), an immunity protein (inactivates its cognate colicin), and lysis protein (aids in colicin release via host cell lysis). Col operons are efficient plasmid-maintenance systems; (i) the plasmid cured cells are killed by the colicins; (ii) damaged cells lyse and releases the colicins that eliminate the competitors; and (iii) the released plasmids invade new bacteria. Surprisingly, some bacterial genomes have Col operons. The eco-evolutionary drive and physiological relevance of genomic Col operons are unknown. We investigated plasmidic and genomic Col operons using sequence analyses from an eco-evolutionary perspective. We found 1,248 genomic and plasmidic colicins across 30 bacterial genera. Although 51% of the genomes harbor colicins, the majority of the genomic colicins lacked a functional lysis gene, suggesting the negative selection of lethal genes. The immunity gene of the Col operon protects the cured host thereby eliminating the metabolic burden due to plasmid. We show mutual exclusivity of col operons on genomes and plasmids. We propose anti-addiction hypothesis for genomic colicins. Using a stochastic agent-based model, we show that the genomic colicins confer an advantage to the host genome in terms of immunity to the toxin and elimination of plasmid burden. Col operons are genetic arms that regulate the ecological interplay of bacterial genomes and plasmids.

scholarly journals FKBP5 Regulates RIG-I-Mediated NF-κB Activation and Influenza A Virus Infection

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 672
Author(s):  
Wenzhuo Hao ◽  
Lingyan Wang ◽  
Shitao Li
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Social Impact ◽  
Respiratory Pathogen ◽  
Innate Immune Responses ◽  
Interferon Stimulated Genes ◽  
Fk506 Binding Protein ◽  
Ikk Complex ◽  
Inducible Gene

Influenza A virus (IAV) is a highly transmissible respiratory pathogen and is a constant threat to global health with considerable economic and social impact. Influenza viral RNA is sensed by host pattern recognition receptors (PRRs), such as the Toll-like receptor 7 (TLR7) and retinoic acid-inducible gene I (RIG-I). The activation of these PRRs instigates the interferon regulatory factor (IRF) and nuclear factor kappa B (NF-κB) signaling pathways that induce the expression of interferon-stimulated genes (ISGs) and inflammatory genes. FK506-binding protein 5 (FKBP5) has been implied in the IκBα kinase (IKK) complex. However, the role of FKBP5 in the RIG-I signaling and IAV infection is not well elucidated. Here, we demonstrate that the knockout of FKBP5 increases IAV infection. Furthermore, FKBP5 binds IKKα, which is critical for RIG-I-induced innate immune responses and ISG expression. Taken together, FKBP5 is a novel anti-influenza host factor that restricts IAV infection by the activation of RIG-I-mediated NF-κB signaling.

scholarly journals Gene Loss and Error-Prone RNA Editing in the Mitochondrion of Perkinsela, an Endosymbiotic Kinetoplastid

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Vojtěch David ◽  
Pavel Flegontov ◽  
Evgeny Gerasimov ◽  
Goro Tanifuji ◽  
Hassan Hashimi ◽  
...  
Keyword(s):  
Rna Editing ◽  
Deep Sequencing ◽  
Gene Loss ◽  
Mitochondrial Rna ◽  
Evolutionary Perspective ◽  
Rna Seq ◽  
Protein Coding ◽  
Mitochondrial Ribosomes ◽  
Protein Coding Genes ◽  
Mitochondrial Transcripts

ABSTRACT Perkinsela is an enigmatic early-branching kinetoplastid protist that lives as an obligate endosymbiont inside Paramoeba (Amoebozoa). We have sequenced the highly reduced mitochondrial genome of Perkinsela, which possesses only six protein-coding genes (cox1, cox2, cox3, cob, atp6, and rps12), despite the fact that the organelle itself contains more DNA than is present in either the host or endosymbiont nuclear genomes. An in silico analysis of two Perkinsela strains showed that mitochondrial RNA editing and processing machineries typical of kinetoplastid flagellates are generally conserved, and all mitochondrial transcripts undergo U-insertion/deletion editing. Canonical kinetoplastid mitochondrial ribosomes are also present. We have developed software tools for accurate and exhaustive mapping of transcriptome sequencing (RNA-seq) reads with extensive U-insertions/deletions, which allows detailed investigation of RNA editing via deep sequencing. With these methods, we show that up to 50% of reads for a given edited region contain errors of the editing system or, less likely, correspond to alternatively edited transcripts. IMPORTANCE Uridine insertion/deletion-type RNA editing, which occurs in the mitochondrion of kinetoplastid protists, has been well-studied in the model parasite genera Trypanosoma, Leishmania, and Crithidia. Perkinsela provides a unique opportunity to broaden our knowledge of RNA editing machinery from an evolutionary perspective, as it represents the earliest kinetoplastid branch and is an obligatory endosymbiont with extensive reductive trends. Interestingly, up to 50% of mitochondrial transcripts in Perkinsela contain errors. Our study was complemented by use of newly developed software designed for accurate mapping of extensively edited RNA-seq reads obtained by deep sequencing.

scholarly journals The Laboratory of Genetics and Physiology 2: Emerging Insights into the Controversial Functions of This RIG-I-Like Receptor

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Zixiang Zhu ◽  
Xiangle Zhang ◽  
Guoqing Wang ◽  
Haixue Zheng
Keyword(s):  
Immune Responses ◽  
Functional Performance ◽  
Signaling Proteins ◽  
Rna Recognition ◽  
Innate Immune Responses ◽  
Downstream Signaling ◽  
Regulation Mechanisms ◽  
Structure And Functions ◽  
Insight Into ◽  
Inducible Gene

The laboratory of genetics and physiology 2 (LGP2) is a key component of the RNA helicase family of retinoic acid-inducible gene 1- (RIG-I-) like receptors (RLRs) and is widely involved in viral RNA recognition and regulation during innate immune responses. Unlike RIG-I and melanoma differentiation-associated 5, both RLR members, LGP2 lacks the caspase-recruitment domain (CARD), which is required for recruiting and interacting with downstream signaling proteins to activate a cascade of downstream signaling events. The absence of the CARD results in divergent functional performance for LGP2 compared to these other RLR members. Both negative and positive regulatory roles have been reported for LGP2 in antiviral immune responses. It is currently unclear how the unusual properties of LGP2 mediate opposing roles. Future studies should elucidate the molecular mechanism(s) of LGP2 action. This minireview provides a brief overview of LGP2 structure and functions, with an expanded discussion on the regulation mechanisms in response to viral infection, hopefully stimulating insight into the divergent roles of LGP2 in the regulation of antiviral immune responses.

scholarly journals Hepatitis E Virus: How It Escapes Host Innate Immunity

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 422
Author(s):  
Sébastien Lhomme ◽  
Marion Migueres ◽  
Florence Abravanel ◽  
Olivier Marion ◽  
Nassim Kamar ◽  
...  
Keyword(s):  
Hepatitis E Virus ◽  
Hepatitis E ◽  
Innate Immune ◽  
Virus Protein ◽  
Intracellular Pathogen ◽  
First Line ◽  
Interferon Stimulated Genes ◽  
The World ◽  
Inducible Gene

Hepatitis E virus (HEV) is a leading cause of viral hepatitis in the world. It is usually responsible for acute hepatitis, but can lead to a chronic infection in immunocompromised patients. The host’s innate immune response is the first line of defense against a virus infection; there is growing evidence that HEV RNA is recognized by toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), leading to interferon (IFN) production. The IFNs activate interferon-stimulated genes (ISGs) to limit HEV replication and spread. HEV has developed strategies to counteract this antiviral response, by limiting IFN induction and signaling. This review summarizes the advances in our knowledge of intracellular pathogen recognition, interferon and inflammatory response, and the role of virus protein in immune evasion.

scholarly journals An alternative model for type I interferon induction downstream of human TLR2

2020 ◽  
Vol 295 (42) ◽  
pp. 14325-14342
Author(s):  
Timo Oosenbrug ◽  
Michel J. van de Graaff ◽  
Mariëlle C. Haks ◽  
Sander van Kasteren ◽  
Maaike E. Ressing
Keyword(s):  
Molecular Mechanisms ◽  
Human Monocyte ◽  
Cell Types ◽  
Type I Interferons ◽  
Type I ◽  
Downstream Signaling ◽  
Interferon Stimulated Genes ◽  
Cytokines And Chemokines ◽  
A Cell ◽  
Extracellular Environment

Surface-exposed Toll-like receptors (TLRs) such as TLR2 and TLR4 survey the extracellular environment for pathogens. TLR activation initiates the production of various cytokines and chemokines, including type I interferons (IFN-I). Downstream of TLR4, IFNβ secretion is only vigorously triggered in macrophages when the receptor undergoes endocytosis and switches signaling adaptor; surface TLR4 engagement predominantly induces proinflammatory cytokines via the signaling adaptor MyD88. It is unclear whether this dichotomy is generally applicable to other TLRs, cell types, or differentiation states. Here, we report that diverse TLR2 ligands induce an IFN-I response in human monocyte-like cells, but not in differentiated macrophages. This TLR2-dependent IFN-I signaling originates from the cell surface and depends on MyD88; it involves combined activation of the transcription factors IRF3 and NF-κB, driven by the kinases TBK1 and TAK1-IKKβ, respectively. TLR2-stimulated monocytes produced modest IFNβ levels that caused productive downstream signaling, reflected by STAT1 phosphorylation and expression of numerous interferon-stimulated genes. Our findings reveal that the outcome of TLR2 signaling includes an IFN-I response in human monocytes, which is lost upon macrophage differentiation, and differs mechanistically from IFN-I-induction through TLR4. These findings point to molecular mechanisms tailored to the differentiation state of a cell and the nature of receptors activated to control and limit TLR-triggered IFN-I responses.

scholarly journals Modeling Colicin Operons as Genetic Arms in Plasmid-genome Conflicts

2021 ◽  
Author(s):  
Pavithra Anantharaman Sudhakari ◽  
Bhaskar Chandra Mohan Ramisetty
Keyword(s):  
Negative Selection ◽  
Bacterial Genome ◽  
Evolutionary Perspective ◽  
Bacterial Genomes ◽  
Sequence Analyses ◽  
Agent Based ◽  
Physiological Relevance ◽  
Maintenance Systems ◽  
Selection Of ◽  
Lethal Genes

Abstract Plasmids are acellular propagating entities that depend on bacteria, as molecular parasites, for propagation. A 'tussle' between bacteria and plasmid ensues; bacteria for riddance of the plasmid and plasmid for persistence within a live host. The conflict between bacterial genome and plasmids allows the emergence of 'genetic arms' such as colicin (Col) operons. Endonuclease Col operons encode three proteins; an endonuclease colicin, an immunity protein, and lysis protein. Col operons are plasmid-maintenance systems; (i) the plasmid-cured cells are killed by the colicins; (ii) damaged cells lyse and release the colicins that eliminate the competitors, and (iii) the released plasmids invade new bacteria. Surprisingly, some bacterial genomes have Col operons. The eco-evolutionary drive and physiological relevance of genomic Col operons are unknown. We investigated plasmidic and genomic Col operons using sequence analyses from an eco-evolutionary perspective. We found 1,248 genomic and plasmidic colicins across 30 bacterial genera. Although 51% of the genomes harbor colicins, the majority of the genomic colicins lacked a functional lysis gene, suggesting the negative selection of lethal genes. The immunity gene of the Col operon protects the plasmid-cured host; eliminating the metabolic burden. We show mutual exclusivity of Col operons on genomes and plasmids. We propose an anti-addiction hypothesis for genomic colicins. Using a stochastic agent-based model, we show that the genomic colicins confer an advantage to the host genome in terms of immunity to the toxin and elimination of plasmid burden. Col operons are 'genetic arms' that regulate the ecological interplay of bacterial genomes and plasmids.

scholarly journals Deciphering the Fine-Tuning of the Retinoic Acid-Inducible Gene-I Pathway in Teleost Fish and Beyond

2021 ◽  
Vol 12 ◽  
Author(s):  
Raphaël Jami ◽  
Emilie Mérour ◽  
Annie Lamoureux ◽  
Julie Bernard ◽  
Jean K. Millet ◽  
...  
Keyword(s):  
Teleost Fish ◽  
Mammalian Species ◽  
Fine Tuning ◽  
Viral Pathogen ◽  
Downstream Signaling ◽  
Pathogen Invasion ◽  
Cellular Factors ◽  
Almost All ◽  
Functional Orthologs ◽  
Inducible Gene

Interferons are the first lines of defense against viral pathogen invasion during the early stages of infection. Their synthesis is tightly regulated to prevent excessive immune responses and possible deleterious effects on the host organism itself. The RIG-I-like receptor signaling cascade is one of the major pathways leading to the production of interferons. This pathway amplifies danger signals and mounts an appropriate innate response but also needs to be finely regulated to allow a rapid return to immune homeostasis. Recent advances have characterized different cellular factors involved in the control of the RIG-I pathway. This has been most extensively studied in mammalian species; however, some inconsistencies remain to be resolved. The IFN system is remarkably well conserved in vertebrates and teleost fish possess all functional orthologs of mammalian RIG-I-like receptors as well as most downstream signaling molecules. Orthologs of almost all mammalian regulatory components described to date exist in teleost fish, such as the widely used zebrafish, making fish attractive and powerful models to study in detail the regulation and evolution of the RIG-I pathway.

scholarly journals Long-term, inducible gene loss-of-function in the chicken embryo

genesis ◽  
2013 ◽  
Vol 51 (5) ◽  
pp. 372-380 ◽  
Author(s):  
Olivier Serralbo ◽  
Cyril A. Picard ◽  
Christophe Marcelle
Keyword(s):  
Chicken Embryo ◽  
Gene Loss ◽  
Loss Of Function ◽  
Inducible Gene

scholarly journals Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease

2012 ◽  
Vol 209 (10) ◽  
pp. 1781-1795 ◽  
Author(s):  
SuJin Hwang ◽  
Ki-Duk Song ◽  
Renaud Lesourne ◽  
Jan Lee ◽  
Julia Pinkhasov ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Negative Selection ◽  
Cell Lineage ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
Chain Gene ◽  
Regulatory Sequences ◽  
Tcr Signaling ◽  
Gene Encoding ◽  
Downstream Signaling

Negative selection and regulatory T (T reg) cell development are two thymus-dependent processes necessary for the enforcement of self-tolerance, and both require high-affinity interactions between the T cell receptor (TCR) and self-ligands. However, it remains unclear if they are similarly impacted by alterations in TCR signaling potential. We generated a knock-in allele (6F) of the TCR ζ chain gene encoding a mutant protein lacking signaling capability whose expression is controlled by endogenous ζ regulatory sequences. Although negative selection was defective in 6F/6F mice, leading to the survival of autoreactive T cells, 6F/6F mice did not develop autoimmune disease. We found that 6F/6F mice generated increased numbers of thymus-derived T reg cells. We show that attenuation of TCR signaling potential selectively impacts downstream signaling responses and that this differential effect favors Foxp3 expression and T reg cell lineage commitment. These results identify a potential compensatory pathway for the enforcement of immune tolerance in response to defective negative selection caused by reduced TCR signaling capability.

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