Biology subjects

Taubert, S.

Publications and source records attributed to Taubert, S..

11 recordsLinked to original sources

bioRxiv2026

C. elegans Nuclear Hormone Receptor NHR-49 promotes attractive chemotaxis independently of its role in fatty acid metabolism

All organisms must sense and adapt to environmental cues to survive and thrive. In the nematode worm Caenorhabditis elegans, the nuclear hormone receptor nhr-49 is required for lipid homeostasis, stress resilience, pathogen defense, and longevity. In addition, recent studies suggest that NHR-49 controls avoidance behaviors and aversive memory to pathogenic bacteria and mitochondrial disruption, acting via its established role in fatty acid desaturation and fatty acid oxidation, respectively. However, the role of NHR-49 in neuronal signaling and behavior remains poorly understood. Here, we uncover a new role for NHR-49 in AWA neuron-mediated attractive chemotaxis. We show that nhr-49 is required for chemotaxis towards diacetyl and pyrazine, two AWA neuron-sensed compounds, but not for AWC- or ASH-mediated chemotaxis. Supplementation with unsaturated fatty acids and mutational analysis of additional genes involved in fatty acid desaturation or {beta}-oxidation reveal that these processes do not affect attractive chemotaxis; this suggests that NHR-49 mediates attractive chemotaxis independently of its role in fatty acid desaturation and oxidation. Tissue-specific expression of NHR-49 in neurons or body wall muscle is sufficient to rescue chemotaxis defects, while nhr-49 depletion in neurons alone causes chemotaxis defects. Finally, nhr-49 mutants also show defects in another behavior, the response and habituation to mechanosensory stimuli. Together, our data reveal new functions for NHR-49 in sensory responses and non-associative learning, which are distinct from its roles in aversive behaviors and memory and, notably, independent of its well-established role in lipid metabolism.

neuroscience↗

bioRxiv2025

Hoi1 targets the yeast BLTP2 protein to ER-PM contact sites to regulate lipid homeostasis

Membrane contact sites between organelles are important for maintaining cellular lipid homeostasis. Members of the recently identified family of bridge-like lipid transfer proteins (BLTPs) span opposing membranes at these contact sites to enable the rapid transfer of bulk lipids between organelles. While the VPS13 and ATG2 family members use organelle-specific adaptors for membrane targeting, the mechanisms that regulate other bridge-like transporters remain unknown. Here, we identify the conserved protein Ybl086c, which we name Hoi1 (Hob interactor 1), as an adaptor that targets the yeast BLTP2-like proteins Fmp27/Hob1 and Hob2 to ER-PM contact sites. Two separate Hoi1 domains interface with alpha-helical projections that decorate the central hydrophobic channel on Fmp27, and loss of these interactions disrupts cellular sterol homeostasis. The mutant phenotypes of BLTP2 and HOI1 orthologs indicate these proteins act in a shared pathway in worms and flies. Together, this suggests that Hoi1-mediated recruitment of BLTP2-like proteins represents an evolutionarily conserved mechanism for regulating lipid transport at membrane contact sites.

cell biology↗

bioRxiv2024

Eukaryotic Elongation Factor 2 Kinase EFK-1/eEF2K promotes starvation resistance by preventing oxidative damage in C. elegans

Cells and organisms frequently experience starvation. To adapt and survive, they mount an evolutionarily conserved stress response. A vital component in the mammalian starvation response is eukaryotic elongation factor 2 (eEF2) kinase (eEF2K), which responds to starvation by phosphorylating and inactivating the translation elongation driver eEF2, thus shutting down translation and facilitating survival. C. elegans efk-1/eEF2K phosphorylates EEF-2/eEF2 on a conserved residue and is required for starvation survival, but how it promotes survival remains unclear. Surprisingly, we found that eEF2 phosphorylation is unchanged in starved C. elegans, suggesting that efk-1 promotes survival via a noncanonical pathway. We show that efk-1 upregulates transcription of the DNA repair pathways, nucleotide excision repair (NER) and base excision repair (BER), to promote starvation survival. Furthermore, efk-1 suppresses oxygen consumption and ROS production in starvation to prevent oxidative stress. Thus, efk-1 enables starvation survival by protecting animals from starvation-induced oxidative damage through a translation-independent pathway.

genetics↗

bioRxiv2023

The unfolded protein response of the endoplasmic reticulum protects Caenorhabditis elegans against DNA damage caused by stalled replication forks

All animals must maintain genome and proteome integrity, especially when experiencing endogenous or exogenous stress. To cope, organisms have evolved sophisticated and conserved response systems: unfolded protein responses (UPRs) ensure proteostasis while DNA damage responses (DDRs) maintains genome integrity. Emerging evidence suggests that UPRs and DDRs crosstalk, but this remains poorly understood. Here, we demonstrate that depletion of the DNA primases pri-1 or pri-2, which synthesize RNA primers at replication forks and whose inactivation causes DNA damage, activates the UPR of the endoplasmic reticulum (UPR-ER) in Caenorhabditis elegans, with especially strong activation in the germline. We observed activation of both the inositol-requiring-enzyme 1 (ire-1) and the protein kinase RNA-like ER kinase (pek-1) branches of the UPR-ER. Interestingly, activation of the UPR-ER output gene heat shock protein 4 (hsp-4) was partially independent of its canonical activators, ire-1 and X-box binding protein (xbp-1), and instead required the third branch of the UPR-ER, activating transcription factor 6 (atf-6), suggesting functional redundancy. We further found that primase depletion specifically induces the UPR-ER, but not the distinct cytosolic or mitochondrial UPRs, suggesting that primase inactivation causes compartment-specific rather than global stress. Functionally, loss of ire-1 or pek-1 sensitized animals to replication stress caused by hydroxyurea. Finally, transcriptome analysis of pri-1 embryos revealed several deregulated processes that could cause UPR-ER activation, including protein glycosylation, calcium signaling, and fatty acid desaturation. Together, our data show that the UPR-ER, but not other UPRs, responds to replication fork stress and that the UPR-ER is required to alleviate this stress.

genetics↗

bioRxiv2022

Mediator subunit MDT-15 promotes expression of propionic acid breakdown genes to prevent embryonic lethality in Caenorhabditis elegans

The micronutrient vitamin B12 is an essential cofactor for two enzymes: methionine synthase, which plays a key role in the one-carbon cycle; and methylmalonyl-CoA mutase, an enzyme in a pathway that breaks down branched-chain amino acids and odd-chain fatty acids. A second, vitamin B12-independent pathway that degrades methylmalonyl-CoA and its upstream metabolite propionic acid was recently described in Caenorhabditis elegans, the propionate shunt pathway. Activation of five shunt pathway genes in response to low vitamin B12 availability or high propionic acid levels is accomplished by a transcriptional regulatory mechanism involving two nuclear hormone receptors, NHR-10 and NHR-68. Here, we report that the C. elegans Mediator subunit mdt-15 is also essential for the activation of the propionate shunt pathway genes, likely by acting as a transcriptional coregulator for NHR-10. C. elegans mdt-15 mutants fed a low vitamin B12 diet have transcriptomes resembling those of wild-type worms fed a high vitamin B12 diet, with low expression of the shunt genes. Phenotypically, the embryonic lethality of mdt-15 mutants is specifically rescued by diets high in vitamin B12, but not by dietary polyunsaturated fatty acids, which rescue many other phenotypes of the mdt-15 mutants. Finally, NHR-10 binds to MDT-15 in yeast-two-hybrid assays, and the transcriptomes of nhr-10 mutants resemble those of mdt-15 mutants. Our data show that MDT-15 is a key coregulator for an NHR regulating propionic acid detoxification, adding to roles played by NHR:MDT-15 partnerships in metabolic regulation and pinpointing vitamin B12 availability as a requirement for mdt-15 dependent embryonic development.

genetics↗

bioRxiv2021

cSurvival: a web resource for biomarker interactions in cancer outcomes

Survival analysis is a technique to identify prognostic biomarkers and genetic vulnerabilities in cancer studies. Large-scale consortium-based projects have profiled >11,000 adult and >4,000 paediatric tumor cases with clinical outcomes and multi-omics approaches. This provides a resource for investigating molecular-level cancer etiologies using clinical correlations. Although cancers often arise from multiple genetic vulnerabilities and have deregulated gene sets (GSs), existing survival analysis protocols can report only on individual genes. Additionally, there is no systematic method to connect clinical outcomes with experimental (cell line) data. To address these gaps, we developed cSurvival (https://tau.cmmt.ubc.ca/cSurvival). cSurvival provides a user-adjustable analytical pipeline with a curated, integrated database, and offers three main advances: (a) joint analysis with two genomic predictors to identify interacting biomarkers, including new algorithms to identify optimal cutoffs for two continuous predictors; (b) survival analysis not only at the gene, but also the GS level; and (c) integration of clinical and experimental cell line studies to generate synergistic biological insights. To demonstrate these advances, we report three case studies. We confirmed findings of autophagy-dependent survival in colorectal cancers and of synergistic negative effects between high expression of SLC7A11 and SLC2A1 on outcomes in several cancers. We further used cSurvival to identify high expression of the Nrf2-antioxidant response element pathway as a main indicator for lung cancer prognosis and for cellular resistance to oxidative stress-inducing drugs. Together, these analyses demonstrate cSurvivals ability to support biomarker prognosis and interaction analysis via gene- and GS-level approaches and to integrate clinical and experimental biomedical studies. Key pointsO_LIWe developed cSurvival, an advanced framework using clinical correlations to study biomarker interactions in cancers, with source code and curated datasets freely available for all C_LIO_LIcSurvival includes new algorithms to identify optimal cutoffs for two continuous predictors to stratify patients into risk groups, enabling for the first time joint analysis with two genomic predictors; C_LIO_LIcSurvival allows survival analysis at the gene set (GS) level with comprehensive and up-to-date GS libraries C_LIO_LIThe cSurvival pipeline integrates clinical outcomes and experimental cancer cell line data to generate synergistic biological insights and to mine for appropriate preclinical cell line tools C_LIO_LIcSurvival is built on a manually curated cancer outcomes database C_LI

genomics↗

bioRxiv2021

Nuclear Hormone Receptor NHR-49 controls a HIF-1-independent hypoxia adaptation pathway in Caenorhabditis elegans

The response to insufficient oxygen (hypoxia) is orchestrated by the conserved Hypoxia-Inducible Factor (HIF). However, HIF-independent hypoxia response pathways exist that act in parallel to HIF to mediate the physiological hypoxia response. Here, we describe a HIF-independent hypoxia response pathway controlled by Caenorhabditis elegans Nuclear Hormone Receptor NHR-49, an orthologue of mammalian Peroxisome Proliferator-Activated Receptor alpha (PPAR). We show that nhr-49 is required for worm survival in hypoxia and is synthetic lethal with hif-1 in this context, demonstrating that these factors act independently. RNA-seq analysis shows that in hypoxia nhr-49 regulates a set of genes that are hif-1-independent, including autophagy genes that promote hypoxia survival. We further show that Nuclear Hormone Receptor nhr-67 is a negative regulator and Homeodomain-interacting Protein Kinase hpk-1 is a positive regulator of the NHR-49 pathway. Together, our experiments define a new, essential hypoxia response pathway that acts in parallel to the well-known HIF-mediated hypoxia response.

genetics↗

bioRxiv2020

NHR-49/PPAR-α and HLH-30/TFEB promote C. elegans host defense via a flavin-containing monooxygenase

During bacterial infection, the host is confronted with multiple overlapping signals that are integrated at the organismal level to produce defensive host responses. How multiple infection signals are sensed by the host and how they elicit the transcription of host defense genes is much less understood at the whole-animal level than at the cellular level. The model organism Caenorhabditis elegans is known to mount transcriptional defense responses against intestinal bacterial infections that elicit overlapping starvation and infection responses, but the regulation of such responses is not well understood. Direct comparison of C. elegans that were starved or infected with Staphylococcus aureus revealed a large infection-specific transcriptional signature. This signature was almost completely abrogated by deletion of transcription factor hlh-30/TFEB, except for six genes including a flavin-containing monooxygenase (FMO) gene, fmo-2/FMO5. Deletion of fmo-2/FMO5 severely compromised infection survival, thus identifying the first FMO with innate immunity functions in animals. Moreover, the mechanism of fmo-2/FMO5 induction required the nuclear hormone receptor, NHR-49/PPAR-, which induced fmo-2/FMO5 and host defense cell non-autonomously. These findings for the first time reveal an infection-specific host response to S. aureus, identify HLH-30/TFEB as its main regulator, reveal that FMOs are important innate immunity effectors in animals, and identify the mechanism of FMO regulation through NHR-49/PPAR- in C. elegans, with important implications for innate host defense in higher organisms.

microbiology↗

bioRxiv2019

ER stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated and is implicated in metabolic diseases when compromised. Using an engineered sensor that exclusively activates the unfolded protein response (UPR) during aberrant ER membrane lipid composition, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and are conserved in C. elegans. To systematically validate yeast mutants disrupting ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensing switch in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation (ChIP) analyses pinpoint the UPR as a broad-spectrum compensatory pathway in which LBS and proteotoxic stress-induced UPR deploy divergent transcriptional programs. Together, these findings reveal the UPR program as the sum of two independent stress events and could be exploited for future therapeutic intervention.

cell biology↗

bioRxiv2019

Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans

Zinc is essential for cellular functions as it is a catalytic and structural component of many proteins. In contrast, cadmium is not required in biological systems and is toxic. Zinc and cadmium levels are closely monitored and regulated as their excess causes cell stress. To maintain homeostasis, organisms induce metal detoxification gene programs through stress responsive transcriptional regulatory complexes. In Caenorhabditis elegans, the MDT-15 subunit of the evolutionarily conserved Mediator transcriptional coregulator is required to induce genes upon exposure to excess zinc and cadmium. However, the regulatory partners of MDT-15 in this response, its role in cellular and physiological stress adaptation, and the putative role mammalian for MED15 in the metal stress responses remain unknown. Here, we show that MDT-15 interacts physically and functionally with the Nuclear Hormone Receptor HIZR-1 to promote molecular, cellular, and organismal adaptation to excess metals. Using gain- and loss-of-function mutants and qPCR and reporter analysis, we find that mdt-15 and hizr-1 cooperate to induce zinc and cadmium responsive genes. Moreover, the two proteins interact physically in yeast-two-hybrid assays and this interaction is enhanced by the addition of zinc or cadmium, the former a known ligand of HIZR-1. Functionally, mdt-15 and hizr-1 mutants show defective storage of excess zinc in the gut, and at the organismal level, mdt-15 mutants are hypersensitive to zinc- and cadmium-induced reductions in egg-laying. Lastly, mammalian MDT-15 orthologs bind genomic regulatory regions of metallothionein and zinc transporter genes in a metal-stimulated fashion, and human MED15 is required to induce a metallothionein gene in lung adenocarcinoma cells exposed to cadmium. Collectively, our data show that mdt-15 and hizr-1 cooperate to regulate metal detoxification and zinc storage and that this mechanism appears to be at least partially conserved in mammals.

genetics↗

bioRxiv2018

C. elegans Mediator 15 permits low temperature-induced longevity via regulation of lipid and protein homeostasis

Low temperatures slow aging and extend lifespan in many organisms, including Caenorhabditis elegans. However, the metabolic and homeostatic aspects of low temperature-induced longevity remain poorly understood. Here, we show that changes in lipid composition regulated by MDT-15/Mediator 15, transcriptional co-regulator, is essential for low temperature-induced longevity and proteostasis in C. elegans. We find that inhibition of mdt-15 prevents animals from living long at low temperatures. We show that MDT-15 up-regulates fat-7, a fatty acid desaturase, at low temperatures, which increases the ratio of unsaturated to saturated fatty acids. We further demonstrate that maintaining this increased fatty acid ratio is essential for protein homeostasis and longevity at low temperatures. Thus, the homeostasis of lipid composition by MDT-15 appears to be a limiting factor for C. elegans proteostasis and longevity at low temperatures. Our findings highlight the crucial roles of fat regulation in maintaining normal organismal physiology under different environmental conditions.

developmental biology↗