Cholesterol Regulates Innate Immunity via Nuclear Hormone Receptor NHR-8

Otarigho, Benson; Aballay, Alejandro

doi:10.1016/j.isci.2021.103361

Cited by 3 publications

(3 citation statements)

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“…Immune effectors that were induced during cholesterol starvation in qRT-PCR studies ( irg-4 , irg-5 , K08D8.4, and T24B8.5) were again found among these differentially regulated genes, confirming the integrity of our RNA-seq analysis ( Figure 3C ). These observations were confirmed in a separate RNA-seq experiment ( Otarigho and Aballay, 2021 ). Importantly, a comparison of the transcriptional changes in nhr-8(hd117 ) mutants with the genes regulated by low cholesterol revealed a remarkable correlation across all genes ( r = 0.578) and differentially expressed genes ( r = 0.836) ( Figure 3—figure supplement 1B ).…”

Section: Resultssupporting

confidence: 60%

Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition

Peterson

Icso

Salisbury

et al. 2022

eLife

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Intracellular signaling regulators can be concentrated into membrane-free, higher-ordered protein assemblies to initiate protective responses during stress - a process known as phase transition. Here, we show that a phase transition of the Caenorhabditis elegans Toll/interleukin-1 receptor domain protein (TIR-1), an NAD+ glycohydrolase homologous to mammalian sterile alpha and TIR motif-containing 1 (SARM1), underlies p38 PMK-1 immune pathway activation in C. elegans intestinal epithelial cells. Through visualization of fluorescently labeled TIR-1/SARM1 protein, we demonstrate that physiologic stresses, both pathogen and non-pathogen, induce multimerization of TIR-1/SARM1 into visible puncta within intestinal epithelial cells. In vitro enzyme kinetic analyses revealed that, like mammalian SARM1, the NAD+ glycohydrolase activity of C. elegans TIR-1 is dramatically potentiated by protein oligomerization and a phase transition. Accordingly, C. elegans with genetic mutations that specifically block either multimerization or the NAD+ glycohydrolase activity of TIR-1/SARM1 fail to induce p38 PMK phosphorylation, are unable to increase immune effector expression, and are dramatically susceptible to bacterial infection. Finally, we demonstrate that a loss-of-function mutation in nhr-8, which alters cholesterol metabolism and is used to study conditions of sterol deficiency, causes TIR-1/SARM1 to oligomerize into puncta in intestinal epithelial cells. Cholesterol scarcity increases p38 PMK-1 phosphorylation, primes immune effector induction in a manner that requires TIR-1/SARM1 oligomerization and its intrinsic NAD+ glycohydrolase activity, and reduces pathogen accumulation in the intestine during a subsequent infection. These data reveal a new adaptive response that allows a metazoan host to anticipate pathogen threats during cholesterol deprivation, a time of relative susceptibility to infection. Thus, a phase transition of TIR-1/SARM1 as a prerequisite for its NAD+ glycohydrolase activity is strongly conserved across millions of years of evolution and is essential for diverse physiological processes in multiple cell types.

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Section: Resultssupporting

confidence: 60%

Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition

Peterson

Icso

Salisbury

et al. 2022

eLife

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“…Nuclear hormone receptors are used in many contexts to systemically coordinate signaling. In C. elegans multiple nhr genes have been linked to innate immunity, including nhr-8, nhr-23, nhr-25, nhr-45, nhr-49, nhr-57, nhr-80, and nhr-112 [55][56][57][58][59][60][61][62]. Thus, this is an interesting family of genes to potentially contribute to differences in organismal response and/or susceptibility in vivo.…”

Section: Changes In Gene Expression By Infection With S Epidermidismentioning

confidence: 99%

Wild-type Caenorhabditis elegans isolates exhibit distinct gene expression profiles in response to microbial infection

2022

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The soil-dwelling nematode Caenorhabditis elegans serves as a model system to study innate immunity against microbial pathogens. C. elegans have been collected from around the world, where they, presumably, adapted to regional microbial ecologies. Here we use survival assays and RNA-sequencing to better understand how two isolates from disparate climates respond to pathogenic bacteria. We found that, relative to N2 (originally isolated in Bristol, UK), CB4856 (isolated in Hawaii), was more susceptible to the Gram-positive microbe, Staphylococcus epidermidis, but equally susceptible to Staphylococcus aureus as well as two Gram-negative microbes, Providencia rettgeri and Pseudomonas aeruginosa. We performed transcriptome analysis of infected worms and found gene-expression profiles were considerably different in an isolate-specific and microbe-specific manner. We performed GO term analysis to categorize differential gene expression in response to S. epidermidis. In N2, genes that encoded detoxification enzymes and extracellular matrix proteins were significantly enriched, while in CB4856, genes that encoded detoxification enzymes, C-type lectins, and lipid metabolism proteins were enriched, suggesting they have different responses to S. epidermidis, despite being the same species. Overall, discerning gene expression signatures in an isolate by pathogen manner can help us to understand the different possibilities for the evolution of immune responses within organisms.

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“…Overexpression of either human SIDT1 or SIDT2, or SID-1 of C. elegans , in HEK293 cells revealed that radiolabeled dsRNA uptake displayed a dose-dependent response to cholesterol addition (82). Furthermore, Innate immunity in C. elegans , which is a cholesterol auxotroph, requires the function of the CHUP-1 cholesterol transporter, a structural but not functional ortholog of SID-1, as well as human SIDT1 and SIDT2 (83, 84). Likewise, it was demonstrated that SIDT2 functions in the endolysosomal transport of dsRNA from different dsRNA-producing viruses in the initiation of the innate immune response, which is impaired in Sidt2 (-/-) knockout mice (24).…”

Section: Discussionmentioning

confidence: 99%

Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models

Nourse

Russell

Moniz

et al. 2022

Preprint

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Whole exome sequencing of Parkinson's disease (PD) patient DNA identified single-nucleotide polymorphisms (SNPs) in the TNK2 gene. Although TNK2 encodes a non-receptor tyrosine kinase that has been shown to prevent the endocytosis of the dopamine reuptake transporter (DAT), a causal role for TNK2 in PD remains unresolved. We postulated that specific recessive mutations in patients resulted in aberrant or prolonged overactivity as a consequence of failed negative regulation by an E3 ubiquitin ligase, NEDD4. Interestingly, the sole Caenorhabditis elegans ortholog of TNK2, termed SID-3, is an established mediator of epigenetic gene silencing and systemic RNA interference facilitated by the SID-1 dsRNA transporter. While SID-3 had no prior association to dopamine neurotransmission in C. elegans, we hypothesized that TNK2/SID-3 represented a node of integrated dopaminergic and epigenetic signaling essential to neuronal homeostasis. Using genetic and chemical modifiers, including a TNK2 inhibitor (AIM-100) and NEDD4 activator (NAB2), in bioassays for dopamine uptake or RNAi in dopaminergic neurons of C. elegans, we determined that sid-3 mutants displayed neuroprotection from 6-hydroxydopamine (6-OHDA) exposure, as did wildtype animals treated with AIM-100 or NAB2. Additionally, NAB2 treatment of rat primary neurons correlated with a reduction of TNK2 levels and the attenuation of 6-OHDA neurotoxicity. Notably, CRISPR-modified nematodes engineered with genomic mutations in sid-3 analogous to PD patient-associated SNPs in TNK2 circumvented the resistance to RNAi characteristic of SID-3 dysfunction and furthermore exhibited enhanced susceptibility to neurodegeneration. This study describes a molecular etiology for PD whereby dysfunctional cellular dynamics, dopaminergic, and epigenetic signaling intersect to cause neurodegeneration.

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Cholesterol Regulates Innate Immunity via Nuclear Hormone Receptor NHR-8

Cited by 3 publications

References 0 publications

Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition

Pathogen infection and cholesterol deficiency activate the C. elegans p38 immune pathway through a TIR-1/SARM1 phase transition

Wild-type Caenorhabditis elegans isolates exhibit distinct gene expression profiles in response to microbial infection

Integrated Regulation of Dopaminergic and Epigenetic Effectors of Neuroprotection in Parkinson’s Disease Models

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