Antagonistic paralogs control a switch between growth and pathogen resistance in C. elegans

Reddy, Kirthi C.; Dror, Tal; Underwood, Ryan; Osman, Guled A.; Elder, Corrina R.; Desjardins, Christopher A.; Cuomo, Christina A.; Barkoulas, Michalis; Troemel, Emily R.

doi:10.1371/journal.ppat.1007528

Cited by 89 publications

(295 citation statements)

References 59 publications

Supporting

Mentioning

285

Contrasting

Order By: Relevance

“…Manual inspection of the mapped reads in the 330 CeNDR strains showed evidence for extensive polymorphisms in the pals-22/pals-25 locus that regulate the IPR transcriptional response [13,14]. In total, we found three major pals-22/pals-25 haplotypes (N2-like, CB4856-like, and WN2002-like) that occur globally ( Fig 2, Table S2).…”

Section: Global Genetic Variation In the Pals-family Is Shaped By Balmentioning

confidence: 92%

“…Moreover, six pals-genes showed higher basal expression in CB4856 compared to N2 ( Fig 3A) (FDR < 0.05). For pals-22 and pals-25, expression is higher in N2 than in CB4856 ( Fig 3A) (FDR < 0.05, Table S5A), which may determine gene expression of other IPR members ( Fig 3B) [14].…”

Section: Basal Pals-gene Expression Differs Between N2 and Cb4856mentioning

confidence: 99%

“…Three antiviral responses are known of which RNA interference (RNAi) and uridylation both target viral RNA for degradation [7,[9][10][11]. The third response, the so-called Intracellular Pathogen Response (IPR), is thought to relieve proteotoxic stress from the infection by the OrV and other intracellular pathogens [12][13][14][15]. The 80 genes involved in the IPR pathway are controlled by pals-22 and pals-25 that function as a molecular switch between growth and antiviral defense.…”

Section: Introductionmentioning

confidence: 99%

“…The 80 genes involved in the IPR pathway are controlled by pals-22 and pals-25 that function as a molecular switch between growth and antiviral defense. The gene pals-22 promotes development and lifespan, whereas pals-25 stimulates pathogen resistance [13,14]. Of the 80 IPR genes that become differentially expressed upon infection, 25 genes belong to the pals-gene family.…”

Section: Introductionmentioning

confidence: 99%

“…Current studies investigating the IPR in C. elegans have focused on the reference genotype Bristol N2 [13,14,16,19]. Here, we investigated genetic variation in the pals-gene family which is specifically expanded in C. elegans (humans and mice only contain a single pals-gene ortholog) [18].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Balancing selection of the Intracellular Pathogen Response in natural Caenorhabditis elegans populations

Sluijs

Bosman

Pankok

et al. 2019

Preprint

View full text Add to dashboard Cite

23 0031317482998 24 Mark.Sterken@wur.nl 25 Our work provides evidence that balancing genetic selection shapes the transcriptional defence against pathogens 48 in C. elegans. The transcriptional and genetic data in this study demonstrate the functional diversity that can 49 develop within antiviral transcriptional responses in natural host populations. 50 Page 3 of 28 Background 51 The continuous battle between host and virus drives host genetic variation to arise in antiviral mechanisms such 52 as transcriptional responses. Regulatory genetic variation affects the viral susceptibility after infection, making 53 some individuals within the population more resistant than others [1-4]. Yet, the universality and mode-of-action 54 of genetic diversity in shaping antiviral transcriptional responses within natural populations remains largely 55 unknown. 56 Caenorhabditis elegans and its natural pathogen Orsay virus (OrV) are used as a powerful genetic 57 model system to study host-virus interactions [5]. OrV is a positive-sense single-stranded RNA virus infecting C. 58 elegans intestinal cells where it causes local disruptions of the cellular structures [5, 6]. Two major groups of 59 antiviral genes respond to viral infection in C. elegans: genes related to the RNA interference (RNAi) pathway 60 [5, 7-12] and genes related to the Intracellular Pathogen Response (IPR) [13-16]. The RNAi pathway activity is 61 controlled by the gene sta-1 which in turn is activated by the viral sensor sid-3 that is hypothesized to directly 62 interact with the Orsay virus [7]. Subsequently, the antiviral RNAi components dcr-1, drh-1, and rde-1 degrade 63 the viral RNA [9], but the RNAi genes themselves remain equally expressed during infection [9, 16]. The IPR 64 counteracts infection by intracellular pathogens (including OrV) and increases the ability to handle proteotoxic 65 stress [13-15]. The gene pals-22 co-operates together with pals-25 to control the IPR pathway by functioning as 66 a molecular switch between growth and antiviral defence. Pals-22 promotes development and lifespan, whereas 67 pals-25 stimulates pathogen resistance. Together pals-22 and pals-25 regulate a set of 80 genes that are 68 upregulated upon intracellular infection including 25 genes in the pals-family and several members of the 69 ubiquitination response [14, 15].. Both pals-22 and pals-25 do not change gene expression following OrV 70 infection. In total, the pals-gene family contains 39 members mostly found in five genetic clusters on 71 chromosome I, III, and V.. Recently, a third antiviral defence was identified which degrades the viral genome 72 after uridylation by the gene cde-1 [17]. Together, these antiviral pathways are key in controlling OrV infection 73 in C. elegans. 74The transcriptional responses following infection have so far been studied in the C. elegans laboratory 75 strain N2, in RNAi deficient mutants in the N2 background such as rde-1 and dcr-1 and in the RNAi-deficient 76 wild isolate JU1580 [7, 9, 10, 13, 14, 16]. These studies indica...

show abstract

Section: Global Genetic Variation In the Pals-family Is Shaped By Balmentioning

confidence: 92%

Section: Basal Pals-gene Expression Differs Between N2 and Cb4856mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Balancing selection of the Intracellular Pathogen Response in natural Caenorhabditis elegans populations

Sluijs

Bosman

Pankok

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

Similarities in the induction of the intracellular pathogen response in Caenorhabditis elegans and the type I interferon response in mammals

Lažetić,

Batachari,

Russell

et al. 2023

BioEssays

Self Cite

View full text Add to dashboard Cite

Although the type‐I interferon (IFN‐I) response is considered vertebrate‐specific, recent findings about the Intracellular Pathogen Response (IPR) in nematode Caenorhabditis elegans indicate that there are similarities between these two transcriptional immunological programs. The IPR is induced during infection with natural intracellular fungal and viral pathogens of the intestine and promotes resistance against these pathogens. Similarly, the IFN‐I response is induced by viruses and other intracellular pathogens and promotes resistance against infection. Whether the IPR and the IFN‐I response evolved in a divergent or convergent manner is an unanswered and exciting question, which could be addressed by further studies of immunity against intracellular pathogens in C. elegans and other simple host organisms. Here we highlight similar roles played by RIG‐I‐like receptors, purine metabolism enzymes, proteotoxic stressors, and transcription factors to induce the IPR and IFN‐I response, as well as the similar consequences of these defense programs on organismal development.

show abstract

Amyloid‐like Aggregation Propensities of Metabolites‐ Homogentisic Acid, N‐Acetyl Aspartic Acid and Isovaleric Acid

Dave,

Jaiswal,

Naseer

et al. 2024

ChemBioChem

View full text Add to dashboard Cite

The transformation of metabolites into amyloidogenic aggregates represent an intriguing dimension in the pathophysiology of metabolic disorders, including alkaptonuria, canavan disease, and isovaleric acidemia. Central to this phenomenon are the metabolites homogentisic acid (HA), N‐acetyl aspartic acid (NAA), and isovaleric acid (IVA), which we found, weave an intricate network of self‐assembled structures. Leveraging an array of microscopy techniques, we traced the morphological behavior of these assemblies that exhibit concentration and time‐dependent morphological transitions from isolated globules to clustered aggregates. MD simulation studies suggest significant role of hydrogen bonding interactions in the aggregation process. While displaying strong amyloidogenic propensity in solution, these aged aggregates were significantly cytotoxic to mouse neural N2a cell lines. In vivo effect in Caenorhabditis elegans (C. elegans) nematode further validated cytotoxicity of aggregates. Our findings provide fresh insights to amyloidogenic nature of HA, NAA, and IVA aggregates and their possible role in associated metabolic disorders such as alkaptonuria, canavan disease and isovaleric acidemia.

show abstract

Antagonistic paralogs control a switch between growth and pathogen resistance in C. elegans

Cited by 89 publications

References 59 publications

Balancing selection of the Intracellular Pathogen Response in natural Caenorhabditis elegans populations

Balancing selection of the Intracellular Pathogen Response in natural Caenorhabditis elegans populations

Similarities in the induction of the intracellular pathogen response in Caenorhabditis elegans and the type I interferon response in mammals

Amyloid‐like Aggregation Propensities of Metabolites‐ Homogentisic Acid, N‐Acetyl Aspartic Acid and Isovaleric Acid

Contact Info

Product

Resources

About