Biology subjects

Troemel, E.

Publications and source records attributed to Troemel, E..

8 recordsLinked to original sources

bioRxiv2025

The C. elegans immune switch proteins PALS-25 and PALS-22 localizeto mitochondria and regulate fragmentation

The nematode C. elegans controls immunity against intracellular pathogens like microsporidia using the pals gene family, which has expanded in C. elegans compared to mammals. pals-22 is a negative regulator that restrains pals-25, which serves as a positive regulator of immunity. pals-22 and pals-25 encode proteins that bind each other and can act in the intestine and epidermis, but their subcellular localization and mechanism of action have not been described. Here we show that PALS-22 and PALS-25 proteins localize to mitochondria, with PALS-25 being required for PALS-22 localization to mitochondria. The C-terminus of PALS-25 is both necessary and sufficient for mitochondrial localization. Loss of PALS-22 causes mitochondrial fragmentation, which occurs after activating the Intracellular Pathogen Response (IPR), a transcriptional program induced by intracellular infection. Mitochondrial fragmentation induced in an independent manner increases resistance against microsporidia infection. Thus, PALS-22/25-mediated fragmentation of mitochondria appears to increase immunity against intracellular infection.

immunology↗

bioRxiv2025

The chromatin remodeler LET-418/Mi-2 regulates the intracellular pathogen response in the C. elegans intestine

Chromatin remodeling provides essential transcriptional regulation for all biological processes. In Caenorhabditis elegans, the chromatin remodeler LET-418, a homolog of the human Mi-2{beta} protein, plays a critical role in regulating development, organogenesis, tissue maintenance, stress resistance and lifespan. LET-418 is part of several chromatin remodeling complexes and contributes significantly to the balance between growth and defense mechanisms, yet its target genes remain unclear. Using DNA methylation profiling, we identified genomic binding sites and associated target genes of LET-418 and its MEC-complex-specific interactor MEP-1 in the intestine. Consistent with their presence in the same complex, the two proteins shared more than half of their target genes. Functional analysis revealed that LET-418 and MEP-1 target genes are highly active in the intestine and are involved in repressing innate immune responses, including the intracellular pathogen response (IPR). Consistently, in let-418 mutants, IPR-induced genes, such as pals-5 or pals-2 are strongly upregulated, in a manner dependent on ZIP-1, a major transcription factor for IPR. Additionally, we found pathogen levels of the natural intracellular intestinal pathogen Nematocida parisii significantly reduced in let-418 mutants, supporting the observation of increased IPR in this mutant. Altogether, these findings reveal a crucial role for LET-418 as a modulator of the IPR, aligning with its role in maintaining the balance between development and defense.

genomics↗

bioRxiv2024

Dynamic Control of Argonautes by a Rapidly Evolving Immunological Switch

Small RNAs, coupled with Argonuate proteins (AGOs), regulate diverse biological processes, including immunity against nucleic acid parasites. C. elegans possesses an expanded repertoire of at least 19 AGOs functioning in an intricate gene regulatory network. Despite their crucial roles, little is known about the regulation of AGOs, and whether their expression levels, tissue specificity, and functions change in response to genetic perturbations or environmental triggers. Here, we report that PALS-22, a member of an unusually expanded protein family in C. elegans, acts as a negative regulator of antiviral RNAi involving the RIG-I homolog. The loss of pals-22 leads to enhanced silencing of transgenes and endogenous dsRNAs. We found that PALS-22 normally suppresses the expression of two AGOs, VSRA-1 and SAGO-2, which are activated by bZIP transcription factor ZIP-1. When pals-22 is eliminated, vsra-1 and sago-2 are upregulated. These AGOs in turn play key roles in defense against foreign genetic elements and intracellular pathogens, respectively. Surprisingly, while in pals-22 mutants immune genes functioning in the intracellular pathogen response (IPR) are upregulated, removing SAGO-2 or the RNA-dependent RNA polymerase RRF-3 in these mutants leads to the downregulation of these genes. This observation contrasts with the typical gene-silencing role of siRNAs. Finally, by analyzing C. elegans wild isolates and lab reference strains, we demonstrate that PALS-22 regulates the expression of several germline AGOs, affecting germline mortality and transgenerational epigenetic inheritance. In summary, PALS-22 is a key genetic node that balances the trade-off between immunity and germline health by modulating the functions of different AGOs, thereby shaping the outputs of the RNAi machinery and the dynamics of epigenetic inheritance.

genetics↗

bioRxiv2024

C. elegans RIG-I-like receptor DRH-1 signals via CARDs to activate anti-viral immunity in intestinal cells

Upon sensing viral RNA, mammalian RIG-I-like receptors activate downstream signals using caspase activation and recruitment domains (CARDs), which ultimately promote transcriptional immune responses that have been well-studied. In contrast, the downstream signaling mechanisms for invertebrate RIG-I-like receptors are much less clear. For example, the Caenorhabditis elegans RIG-I-like receptor DRH-1 lacks annotated CARDs and upregulates the distinct output of RNA interference (RNAi). Here we found that, similar to mammal RIG-I-like receptors, DRH-1 signals through two tandem caspase activation and recruitment domains (2CARD) to induce a transcriptional immune response. Expression of DRH-1(2CARD) alone in the intestine was sufficient to induce immune gene expression, increase viral resistance, and promote thermotolerance, a phenotype previously associated with immune activation. We also found that DRH-1 is required in the intestine to induce immune gene expression, and we demonstrate subcellular colocalization of DRH-1 puncta with double-stranded RNA inside the cytoplasm of intestinal cells upon viral infection. Altogether, our results reveal mechanistic and spatial insights into anti-viral signaling in C. elegans, highlighting unexpected parallels in RIG-I-like receptor signaling between C. elegans and mammals. SignificanceViruses are ubiquitous pathogens that challenge diverse organisms, from bacteria to killer whales. While anti-viral defense has been well-studied in mammals, less is known about defense in invertebrates, including the roundworm Caenorhabditis elegans. Here we show that the C. elegans viral sensor DRH-1 shares similarities to a viral sensor in mammals called RIG-I. We find that DRH-1 has a signaling motif resembling the 2CARD motif, which is found in RIG-I and activates anti-viral immunity. We demonstrate that overexpression of DRH-1(2CARD) in C. elegans promotes resistance to viral infection, and that DRH-1 forms clusters inside intestinal cells during viral infection, similar to RIG-I in humans. Overall, these findings provide insights into C. elegans anti-viral immunity, highlighting similarities with mammalian anti-viral immunity.

immunology↗

bioRxiv2023

CUL-6/cullin ubiquitin ligase-mediated degradation of HSP-90 by intestinal lysosomes promotes thermotolerance

Heat shock can be a lethal stressor. Previously, we described a CUL-6/cullin-ring ubiquitin ligase complex in the nematode Caenorhabditis elegans that is induced by intracellular intestinal infection and proteotoxic stress, and that promotes improved survival upon heat shock (thermotolerance). Here, we show that CUL-6 promotes thermotolerance by targeting the heat shock protein HSP-90 for degradation. We show that CUL-6-mediated lowering of HSP-90 protein levels, specifically in the intestine, provides a thermotolerance benefit independent of heat shock factor HSF-1. Furthermore, we show that lysosomal function is required for CUL-6-mediated promotion of thermotolerance and that CUL-6 directs HSP-90 to lysosome-related organelles upon heat shock. Altogether, these results indicate that a CUL-6 ubiquitin ligase promotes organismal survival upon heat shock by promoting HSP-90 degradation in intestinal lysosomes. Thus, HSP-90, a protein commonly associated with protection against heat shock and promoting degradation of other proteins, is actually itself degraded to protect against heat shock.

cell biology↗

bioRxiv2023

Impairment of the SKN-1A/NRF1 proteasome surveillance pathway triggers tissue-specific protective immune responses against distinct natural pathogens in C. elegans.

Protein quality control pathways play important roles in resistance against pathogen infection. For example, the conserved transcription factor SKN-1/NRF upregulates proteostasis capacity after blockade of the proteasome, and also promotes resistance against bacterial infection in the nematode C. elegans. SKN-1/NRF has three isoforms, and the SKN-1A/NRF1 isoform in particular regulates proteasomal gene expression upon proteasome dysfunction as part of a conserved bounce-back response. We report here that, in contrast to the previously reported role of SKN-1 in promoting resistance against bacterial infection, loss-of-function mutants in skn-1a and its activating enzymes ddi-1 and png-1, show constitutive expression of immune response programmes against natural eukaryotic pathogens of C. elegans. These programmes are the Oomycete Recognition Response (ORR), which promotes resistance against oomycetes that infect through the epidermis, and the Intracellular Pathogen Response (IPR), which promotes resistance against intestine-infecting microsporidia. Consequently, skn-1a mutants show increased resistance to both oomycete and microsporidia infections. We also report that almost all ORR/IPR genes induced in common between these programmes are regulated by the proteasome and interestingly, specific ORR/IPR genes can be induced in distinct tissues depending on the exact trigger. Furthermore, we show that increasing proteasome function significantly reduces oomycete-mediated induction of multiple ORR markers. Altogether, our findings demonstrate that proteasome regulation keeps innate immune responses in check in a tissue-specific manner, against natural eukaryotic pathogens of the C. elegans epidermis and intestine.

immunology↗

bioRxiv2019

The C. elegans RIG-I homolog drh-1 mediates the Intracellular Pathogen Response upon viral infection

Mammalian RIG-I-like receptors detect viral dsRNA and 5 triphosphorylated RNA to activate transcription of interferon genes and promote antiviral defense. The C. elegans RIG-I-like receptor DRH-1 promotes defense through antiviral RNA interference, but less is known about its role in regulating transcription. Here we describe a role for drh-1 in directing a transcriptional response in C. elegans called the Intracellular Pathogen Response (IPR), which is associated with increased pathogen resistance. The IPR includes a set of genes induced by diverse stimuli including intracellular infection and proteotoxic stress. Previous work suggested that the proteotoxic stress caused by intracellular infections might be the common trigger of the IPR, but here we demonstrate that different stimuli act through distinct pathways. Specifically, we demonstrate that DRH-1/RIG-I is required for inducing the IPR in response to Orsay virus infection, but not in response to other triggers like microsporidian infection or proteotoxic stress. Furthermore, drh-1 appears to be acting independently of its known role in RNAi. Interestingly, expression of the replication competent Orsay virus RNA1 segment alone is sufficient to induce most of the IPR genes in a manner dependent on RNA dependent RNA polymerase activity and on drh-1. Altogether, these results suggest that DRH-1 is a pattern-recognition receptor that detects viral replication products to activate the IPR stress/immune program in C. elegans.\n\nImportanceC. elegans lacks homologs of most mammalian pattern recognition receptors, and how nematodes detect pathogens is poorly understood. We show that the C. elegans RIG-I homolog drh-1 mediates induction of the Intracellular Pathogen Response (IPR), a novel transcriptional defense program, in response to infection by the natural C. elegans viral pathogen Orsay virus. drh-1 appears to act as a pattern-recognition receptor to induce the IPR transcriptional defense program by sensing the products of viral RNA-dependent RNA polymerase activity. Interestingly, this signaling role of drh-1 is separable from its previously known role in antiviral RNAi. In addition, we show that there are multiple host pathways for inducing the IPR, shedding light on the regulation of this novel transcriptional immune response.

microbiology↗

bioRxiv2018

Natural variation in the C. elegans autophagy response and clearance of intracellular microsporidia

Natural genetic variation can determine the outcome of an infection, and often reflects the co-evolutionary battle between hosts and pathogens. We previously found that a natural variant of the nematode Caenorhabditis elegans from Hawaii (HW) has increased resistance against natural microsporidian pathogens in the Nematocida genus, when compared to the standard laboratory strain of N2. In particular, HW animals can clear infection, while N2 animals cannot. In addition, HW animals have lower levels of intracellular colonization of Nematocida compared to N2. Here we investigate how this natural variation in resistance relates to autophagy. We found that there is much better targeting of autophagy-related machinery to parasites under conditions where they are cleared. In particular, ubiquitin targeting to Nematocida cells correlates very well with their subsequent clearance in terms of timing, host strain and age, as well as Nematocida species. Furthermore, clearance correlates with targeting of the LGG-2/LC3 autophagy protein to parasite cells, with HW animals having much more efficient targeting of LGG-2 to parasite cells than N2 animals. Surprisingly, however, we found that lgg-2 is not required to clear infection. Instead we found that loss of lgg-2 leads to increased intracellular colonization in the HW background, although interestingly, it does not affect colonization in the N2 background. Altogether our results suggest that there is natural genetic variation in an lgg-2-dependent process that regulates intracellular levels of microsporidia at a very early stage of infection prior to clearance.

immunology↗