Insight
is our reward
Search

Publications in Biomedical Research by NOMIS researchers

Identification and structure of an extracellular contractile injection system from the marine bacterium Algoriphagus machipongonensis

NOMIS Researcher(s)

Published in

March 1, 2022

Contractile injection systems (CISs) are phage tail-like nanomachines, mediating bacterial cell–cell interactions as either type VI secretion systems (T6SSs) or extracellular CISs (eCISs). Bioinformatic studies uncovered a phylogenetic group of hundreds of putative CIS gene clusters that are highly diverse and widespread; however, only four systems have been characterized. Here we studied a putative CIS gene cluster in the marine bacterium Algoriphagus machipongonensis. Using an integrative approach, we show that the system is compatible with an eCIS mode of action. Our cryo-electron microscopy structure revealed several features that differ from those seen in other CISs: a ‘cap adaptor’ located at the distal end, a ‘plug’ exposed to the tube lumen, and a ‘cage’ formed by massive extensions of the baseplate. These elements are conserved in other CISs, and our genetic tools identified that they are required for assembly, cargo loading and function. Furthermore, our atomic model highlights specific evolutionary hotspots and will serve as a framework for understanding and re−engineering CISs.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1038/s41564-022-01059-2

Structure of a thylakoid-anchored contractile injection system in multicellular cyanobacteria

NOMIS Researcher(s)

Published in

March 1, 2022

Contractile injection systems (CISs) mediate cell–cell interactions by phage tail-like structures, using two distinct modes of action: extracellular CISs are released into the medium, while type 6 secretion systems (T6SSs) are attached to the cytoplasmic membrane and function upon cell–cell contact. Here, we characterized a CIS in the multicellular cyanobacterium Anabaena, with features distinct from extracellular CISs and T6SSs. Cryo-electron tomography of focused ion beam-milled cells revealed that CISs were anchored in thylakoid membrane stacks, facing the cell periphery. Single particle cryo-electron microscopy showed that this unique in situ localization was mediated by extensions of tail fibre and baseplate components. On stress, cyanobacteria induced the formation of ghost cells, presenting thylakoid-anchored CISs to the environment. Functional assays suggest that these CISs may mediate ghost cell formation and/or interactions of ghost cells with other organisms. Collectively, these data provide a framework for understanding the evolutionary re-engineering of CISs and potential roles of these CISs in cyanobacterial programmed cell death.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1038/s41564-021-01055-y

Structural basis for channel conduction in the pump-like channelrhodopsin ChRmine

NOMIS Researcher(s)

Published in

February 17, 2022

ChRmine, a recently discovered pump-like cation-conducting channelrhodopsin, exhibits puzzling properties (large photocurrents, red-shifted spectrum, and extreme light sensitivity) that have created new opportunities in optogenetics. ChRmine and its homologs function as ion channels but, by primary sequence, more closely resemble ion pump rhodopsins; mechanisms for passive channel conduction in this family have remained mysterious. Here, we present the 2.0 Ã… resolution cryo-EM structure of ChRmine, revealing architectural features atypical for channelrhodopsins: trimeric assembly, a short transmembrane-helix 3, a twisting extracellular-loop 1, large vestibules within the monomer, and an opening at the trimer interface. We applied this structure to design three proteins (rsChRmine and hsChRmine, conferring further red-shifted and high-speed properties, respectively, and frChRmine, combining faster and more red-shifted performance) suitable for fundamental neuroscience opportunities. These results illuminate the conduction and gating of pump-like channelrhodopsins and point the way toward further structure-guided creation of channelrhodopsins for applications across biology.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.cell.2022.01.007

Microfluidic characterisation reveals broad range of SARS-CoV-2 antibody affinity in human plasma

NOMIS Researcher(s)

Published in

February 1, 2022

The clinical outcome of SARS-CoV-2 infections, which can range from asymptomatic to lethal, is crucially shaped by the concentration of antiviral antibodies and by their affinity to their targets. However, the affinity of polyclonal antibody responses in plasma is difficult to measure. Here we used microfluidic antibody affinity profiling (MAAP) to determine the aggregate affinities and concentrations of anti-SARS-CoV-2 antibodies in plasma samples of 42 seropositive individuals, 19 of which were healthy donors, 20 displayed mild symptoms, and 3 were critically ill. We found that dissociation constants, Kd, of anti-receptor-binding domain antibodies spanned 2.5 orders of magnitude from sub-nanomolar to 43 nM. Using MAAP we found that antibodies of seropositive individuals induced the dissociation of pre-formed spike-ACE2 receptor complexes, which indicates that MAAP can be adapted as a complementary receptor competition assay. By comparison with cytopathic effect-based neutralisation assays, we show that MAAP can reliably predict the cellular neutralisation ability of sera, which may be an important consideration when selecting the most effective samples for therapeutic plasmapheresis and tracking the success of vaccinations.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.26508/lsa.202101270

Cooperative defenses during enteropathogenic infection

NOMIS Researcher(s)

Published in

February 1, 2022

During their co-evolution with pathogens, hosts acquired defensive health strategies that allow them to maintain their health or promote recovery when challenged with infections. The cooperative defense system is a largely unexplored branch of these evolved defense strategies. Cooperative defenses limit physiological damage and promote health without having a negative impact on a pathogen’s ability to survive and replicate within the host. Here, we review recent discoveries in the new field of cooperative defenses using the model pathogens Citrobacter rodentium and Salmonella enterica. We discuss not only host-encoded but also pathogen-encoded mechanisms of cooperative defenses. Cooperative defenses remain an untapped resource in clinical medicine. With a global pandemic exacerbated by a lack of vaccine access and a worldwide rise in antibiotic resistance, the study of cooperative defenses offers an opportunity to safeguard health in the face of pathogenic infection.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1016/j.mib.2021.11.003

The Impact of Mouthwash on the Oropharyngeal Microbiota of Men Who Have Sex with Men: a Substudy of the OMEGA Trial

NOMIS Researcher(s)

Published in

February 1, 2022

Mouthwash is a commonly used product and has been proposed as an alternative intervention to prevent gonorrhea transmission. However, the long-term effects of mouthwash on the oral microbiota are largely unknown. We investigated the impact of 12 weeks of daily mouthwash use on the oropharyngeal microbiota in a subset of men who have sex with men who participated in a randomized trial comparing the efficacy of two alcohol-free mouthwashes for the prevention of gonorrhea. We characterized the oropharyngeal microbiota using 16S rRNA gene sequencing of tonsillar fossae samples collected before and after 12 weeks of daily use of Listerine mouthwash or Biotène dry mouth oral rinse. Permutational multivariate analysis of variance (PERMANOVA) was used to assess differences in oropharyngeal microbiota composition following mouthwash use. Differential abundance testing was performed using ALDEx2, with false-discovery rate correction. A total of 306 samples from 153 men were analyzed (Listerine, n = 78 and Biotène, n = 75). There was no difference in the overall structure of the oropharyngeal microbiota following Listerine or Biotène use (PERMANOVA P = 0.413 and P = 0.331, respectively). Although no bacterial taxa were significantly differentially abundant following Listerine use, we observed a small but significant decrease in the abundance of both Streptococcus and Leptotrichia following Biotène use. Overall, our findings suggest that daily use of antiseptic mouthwash has minimal long-term effects on the composition of the oropharyngeal microbiota. IMPORTANCE Given the role of the oral microbiota in human health, it is important to understand if and how external factors influence its composition. Mouthwash use is common in some populations, and the use of antiseptic mouthwash has been proposed as an alternative intervention to prevent gonorrhea transmission. However, the long-term effect of mouthwash use on the oral microbiota composition is largely unknown. We found that daily use of two different commercially available mouthwashes had limited long-term effects on the composition of the oropharyngeal microbiota over a 12-week period. The results from our study and prior studies highlight that different mouthwashes may differentially affect the oral microbiome composition and that further studies are needed to determine if mouthwash use induces short-term changes to the oral microbiota that may have detrimental effects.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1128/spectrum.01757-21

Unique mobile elements and scalable gene flow at the prokaryote–eukaryote boundary revealed by circularized Asgard archaea genomes

NOMIS Researcher(s)

Published in

February 1, 2022

Eukaryotic genomes are known to have garnered innovations from both archaeal and bacterial domains but the sequence of events that led to the complex gene repertoire of eukaryotes is largely unresolved. Here, through the enrichment of hydrothermal vent microorganisms, we recovered two circularized genomes of Heimdallarchaeum species that belong to an Asgard archaea clade phylogenetically closest to eukaryotes. These genomes reveal diverse mobile elements, including an integrative viral genome that bidirectionally replicates in a circular form and aloposons, transposons that encode the 5,000 amino acid-sized proteins Otus and Ephialtes. Heimdallaechaeal mobile elements have garnered various genes from bacteria and bacteriophages, likely playing a role in shuffling functions across domains. The number of archaea- and bacteria-related genes follow strikingly different scaling laws in Asgard archaea, exhibiting a genome size-dependent ratio and a functional division resembling the bacteria- and archaea-derived gene repertoire across eukaryotes. Bacterial gene import has thus likely been a continuous process unaltered by eukaryogenesis and scaled up through genome expansion. Our data further highlight the importance of viewing eukaryogenesis in a pan-Asgard context, which led to the proposal of a conceptual framework, that is, the Heimdall nucleation–decentralized innovation–hierarchical import model that accounts for the emergence of eukaryotic complexity.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1038/s41564-021-01039-y

Disentangling cadherin-mediated cell-cell interactions in collective cancer cell migration

NOMIS Researcher(s)

Published in

January 4, 2022

Cell dispersion from a confined area is fundamental in a number of biological processes, including cancer metastasis. To date, a quantitative understanding of the interplay of single-cell motility, cell proliferation, and intercellular contacts remains elusive. In particular, the role of E- and N-cadherin junctions, central components of intercellular contacts, is still controversial. Combining theoretical modeling with in vitro observations, we investigate the collective spreading behavior of colonies of human cancer cells (T24). The spreading of these colonies is driven by stochastic single-cell migration with frequent transient cell-cell contacts. We find that inhibition of E- and N-cadherin junctions decreases colony spreading and average spreading velocities, without affecting the strength of correlations in spreading velocities of neighboring cells. Based on a biophysical simulation model for cell migration, we show that the behavioral changes upon disruption of these junctions can be explained by reduced repulsive excluded volume interactions between cells. This suggests that in cancer cell migration, cadherin-based intercellular contacts sharpen cell boundaries leading to repulsive rather than cohesive interactions between cells, thereby promoting efficient cell spreading during collective migration.

Research field(s)
Health Sciences, Biomedical Research, Biophysics

DOI
10.1016/j.bpj.2021.12.006

Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition

NOMIS Researcher(s)

Published in

January 1, 2022

While acetylated, RNA-binding-deficient TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) comprised of TDP-43-containing liquid outer shells and liquid centres of HSP70-family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we show that transient oxidative stress, proteasome inhibition or inhibition of the ATP-dependent chaperone activity of HSP70 provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independently of RNA binding or stress granules. Isotope labelling mass spectrometry was used to identify that phase-separated cytoplasmic TDP-43 is bound by the small heat-shock protein HSPB1. Binding is direct, mediated through TDP-43’s RNA binding and low-complexity domains. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and is essential for disassembly of stress-induced TDP-43 droplets. A decrease in HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion was identified in spinal motor neurons of patients with ALS containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41556-022-00988-8

Correlative all-optical quantification of mass density and mechanics of sub-cellular compartments with fluorescence specificity

NOMIS Researcher(s)

Published in

January 1, 2022

Quantitative measurements of physical parameters become increasingly important for understanding biological processes. Brillouin microscopy (BM) has recently emerged as one technique providing the 3D distribution of viscoelastic properties inside biological samples — so far relying on the implicit assumption that refractive index (RI) and density can be neglected. Here, we present a novel method (FOB microscopy) combining BM with optical diffraction tomography and epi-fluorescence imaging for explicitly measuring the Brillouin shift, RI and absolute density with specificity to fluorescently labeled structures. We show that neglecting the RI and density might lead to erroneous conclusions. Investigating the nucleoplasm of wild-type HeLa cells, we find that it has lower density but higher longitudinal modulus than the cytoplasm. Thus, the longitudinal modulus is not merely sensitive to the water content of the sample — a postulate vividly discussed in the field. We demonstrate the further utility of FOB on various biological systems including adipocytes and intracellular membraneless compartments. FOB microscopy can provide unexpected scientific discoveries and shed quantitative light on processes such as phase separation and transition inside living cells.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.7554/eLife.68490

Cultivation of a vampire: ‘Candidatus Absconditicoccus praedator’

NOMIS Researcher(s)

Published in

January 1, 2022

Halorhodospira halophila, one of the most-xerophilic halophiles, inhabits biophysically stressful and energetically expensive, salt-saturated alkaline brines. Here, we report an additional stress factor that is biotic: a diminutive Candidate-Phyla-Radiation bacterium, that we named ‘Ca. Absconditicoccus praedator’ M39-6, which predates H. halophila M39-5, an obligately photosynthetic, anaerobic purple-sulfur bacterium. We cultivated this association (isolated from the hypersaline alkaline Lake Hotontyn Nur, Mongolia) and characterized their biology. ‘Ca. Absconditicoccus praedator’ is the first stably cultivated species from the candidate class-level lineage Gracilibacteria (order-level lineage Absconditabacterales). Its closed-and-curated genome lacks genes for the glycolytic, pentose phosphate- and Entner–Doudoroff pathways which would generate energy/reducing equivalents and produce central carbon currencies. Therefore, ‘Ca. Absconditicoccus praedator’ is dependent on host-derived building blocks for nucleic acid-, protein-, and peptidoglycan synthesis. It shares traits with (the uncultured) ‘Ca. Vampirococcus lugosii’, which is also of the Gracilibacteria lineage. These are obligate parasitic lifestyle, feeding on photosynthetic anoxygenic Gammaproteobacteria, and absorption of host cytoplasm. Commonalities in their genomic composition and structure suggest that the entire Absconditabacterales lineage consists of predatory species which act to cull the populations of their respective host bacteria. Cultivation of vampire : host associations can shed light on unresolved aspects of their metabolism and ecosystem dynamics at life-limiting extremes.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1111/1462-2920.15823

Strategic disinformation outperforms honesty in competition for social influence

NOMIS Researcher(s)

Published in

December 17, 2021

Competition for social influence is a major force shaping societies, from baboons guiding their troop in different directions, to politicians competing for voters, to influencers competing for attention on social media. Social influence is invariably a competitive exercise with multiple influencers competing for it. We study which strategy maximizes social influence under competition. Applying game theory to a scenario where two advisers compete for the attention of a client, we find that the rational solution for advisers is to communicate truthfully when favored by the client, but to lie when ignored. Across seven pre-registered studies, testing 802 participants, such a strategic adviser consistently outcompeted an honest adviser. Strategic dishonesty outperformed truth-telling in swaying individual voters, the majority vote in anonymously voting groups, and the consensus vote in communicating groups. Our findings help explain the success of political movements that thrive on disinformation, and vocal underdog politicians with no credible program.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.isci.2021.103505

Anti-prothrombin autoantibodies enriched after infection with SARS-CoV-2 and influenced by strength of antibody response against SARS-CoV-2 proteins

NOMIS Researcher(s)

Published in

December 1, 2021

Antiphospholipid antibodies (aPL), assumed to cause antiphospholipid syndrome (APS), are notorious for their heterogeneity in targeting phospholipids and phospholipid-binding proteins. The persistent presence of Lupus anticoagulant and/or aPL against cardiolipin and/or β2 glycoprotein I have been shown to be independent risk factors for vascular thrombosis and pregnancy morbidity in APS. aPL production is thought to be triggered by–among other factors–viral infections, though infection-associated aPL have mostly been considered non-pathogenic. Recently, the potential pathogenicity of infection-associated aPL has gained momentum since an increasing number of patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been described with coagulation abnormalities and hyperinflammation, together with the presence of aPL. Here, we present data from a multicentric, mixed-severity study including three cohorts of individuals who contracted SARS-CoV-2 as well as non-infected blood donors. We simultaneously measured 10 different criteria and non-criteria aPL (IgM and IgG) by using a line immunoassay. Further, IgG antibody response against three SARS-CoV-2 proteins was investigated using tripartite automated blood immunoassay technology. Our analyses revealed that selected non-criteria aPL were enriched concomitant to or after an infection with SARS-CoV-2. Linear mixed-effects models suggest an association of aPL with prothrombin (PT). The strength of the antibody response against SARS-CoV-2 was further influenced by SARS-CoV-2 disease severity and sex of the individuals. In conclusion, our study is the first to report an association between disease severity, anti-SARS-CoV-2 immunoreactivity, and aPL against PT in patients with SARS-CoV-2.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1371/journal.ppat.1010118

Wild cereal grain consumption among Early Holocene foragers of the Balkans predates the arrival of agriculture

NOMIS Researcher(s)

Published in

December 1, 2021

Forager focus on wild cereal plants has been documented in the core zone of domestication in southwestern Asia, while evidence for forager use of wild grass grains remains sporadic elsewhere. In this paper, we present starch grain and phytolith analyses of dental calculus from 60 Mesolithic and Early Neolithic individuals from five sites in the Danube Gorges of the central Balkans. This zone was inhabited by likely complex Holocene foragers for several millennia before the appearance of the first farmers ~6200 cal BC. We also analyzed forager ground stone tools for evidence of plant processing. Our results based on the study of dental calculus show that certain species of Poaceae (species of the genus Aegilops) were used since the Early Mesolithic, while ground stone tools exhibit traces of a developed grass grain processing technology. The adoption of domesticated plants in this region after ~6500 cal BC might have been eased by the existing familiarity with wild cereals.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.7554/eLife.72976

Alpha-Synuclein defects autophagy by impairing SNAP29-mediated autophagosome-lysosome fusion

NOMIS Researcher(s)

Published in

December 1, 2021

Dopaminergic (DA) cell death in Parkinson’s disease (PD) is associated with the gradual appearance of neuronal protein aggregates termed Lewy bodies (LBs) that are comprised of vesicular membrane structures and dysmorphic organelles in conjunction with the protein alpha-Synuclein (α-Syn). Although the exact mechanism of neuronal aggregate formation and death remains elusive, recent research suggests α-Syn-mediated alterations in the lysosomal degradation of aggregated proteins and organelles – a process termed autophagy. Here, we used a combination of molecular biology and immunochemistry to investigate the effect of α-Syn on autophagy turnover in cultured human DA neurons and in human post-mortem brain tissue. We found α-Syn overexpression to reduce autophagy turnover by compromising the fusion of autophagosomes with lysosomes, thus leading to a decrease in the formation of autolysosomes. In accord with a compensatory increase in the plasma membrane fusion of autophagosomes, α-Syn enhanced the number of extracellular vesicles (EV) and the abundance of autophagy-associated proteins in these EVs. Mechanistically, α-Syn decreased the abundance of the v-SNARE protein SNAP29, a member of the SNARE complex mediating autophagolysosome fusion. In line, SNAP29 knockdown mimicked the effect of α-Syn on autophagy whereas SNAP29 co-expression reversed the α-Syn-induced changes on autophagy turnover and EV release and ameliorated DA neuronal cell death. In accord with our results from cultured neurons, we found a stage-dependent reduction of SNAP29 in SNc DA neurons from human post-mortem brain tissue of Lewy body pathology (LBP) cases. In summary, our results thus demonstrate a previously unknown effect of α-Syn on intracellular autophagy-associated SNARE proteins and, as a consequence, a reduced autolysosome fusion. As such, our findings will therefore support the investigation of autophagy-associated pathological changes in PD

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1038/s41419-021-04138-0

A selectable all-in-one CRISPR prime editing piggyBac transposon allows for highly efficient gene editing in human cell lines

NOMIS Researcher(s)

Published in

December 1, 2021

CRISPR prime-editors are emergent tools for genome editing and offer a versatile alternative approach to HDR-based genome engineering or DNA base-editors. However, sufficient prime-editor expression levels and availability of optimized transfection protocols may affect editing efficiencies, especially in hard-to-transfect cells like hiPSC. Here, we show that piggyBac prime-editing (PB-PE) allows for sustained expression of prime-editors. We demonstrate proof-of-concept for PB-PE in a newly designed lentiviral traffic light reporter, which allows for estimation of gene correction and defective editing resulting in indels, based on expression of two different fluorophores. PB-PE can prime-edit more than 50% of hiPSC cells after antibiotic selection. We also show that improper design of pegRNA cannot simply be overcome by extended expression, but PB-PE allows for estimation of effectiveness of selected pegRNAs after few days of cultivation time. Finally, we implemented PB-PE for efficient editing of an amyotrophic lateral sclerosis-associated mutation in the SOD1-gene of patient-derived hiPSC. Progress of genome editing can be monitored by Sanger-sequencing, whereas PB-PE vectors can be removed after editing and excised cells can be enriched by fialuridine selection. Together, we present an efficient prime-editing toolbox, which can be robustly used in a variety of cell lines even when non-optimized transfection-protocols are applied.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41598-021-01689-2

Mechanistic insight into bacterial entrapment by septin cage reconstitution

NOMIS Researcher(s)

Published in

December 1, 2021

Septins are cytoskeletal proteins that assemble into hetero-oligomeric complexes and sense micron-scale membrane curvature. During infection with Shigella flexneri, an invasive enteropathogen, septins restrict actin tail formation by entrapping bacteria in cage-like structures. Here, we reconstitute septin cages in vitro using purified recombinant septin complexes (SEPT2-SEPT6-SEPT7), and study how these recognize bacterial cells and assemble on their surface. We show that septin complexes recognize the pole of growing Shigella cells. An amphipathic helix domain in human SEPT6 enables septins to sense positively curved membranes and entrap bacterial cells. Shigella strains lacking lipopolysaccharide components are more efficiently entrapped in septin cages. Finally, cryo-electron tomography of in vitro cages reveals how septins assemble as filaments on the bacterial cell surface.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41467-021-24721-5

Identification of long-lived proteins in the mitochondria reveals increased stability of the electron transport chain

NOMIS Researcher(s)

Published in

November 8, 2021

In order to combat molecular damage, most cellular proteins undergo rapid turnover. We have previously identified large nuclear protein assemblies that can persist for years in post-mitotic tissues and are subject to age-related decline. Here, we report that mitochondria can be long lived in the mouse brain and reveal that specific mitochondrial proteins have half-lives longer than the average proteome. These mitochondrial long-lived proteins (mitoLLPs) are core components of the electron transport chain (ETC) and display increased longevity in respiratory supercomplexes. We find that COX7C, a mitoLLP that forms a stable contact site between complexes I and IV, is required for complex IV and supercomplex assembly. Remarkably, even upon depletion of COX7C transcripts, ETC function is maintained for days, effectively uncoupling mitochondrial function from ongoing transcription of its mitoLLPs. Our results suggest that modulating protein longevity within the ETC is critical for mitochondrial proteome maintenance and the robustness of mitochondrial function.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.devcel.2021.10.008

Glycine-Rich Peptides from FUS Have an Intrinsic Ability to Self-Assemble into Fibers and Networked Fibrils

NOMIS Researcher(s)

Published in

November 2, 2021

Glycine-rich regions feature prominently in intrinsically disordered regions (IDRs) of proteins that drive phase separation and the regulated formation of membraneless biomolecular condensates. Interestingly, the Gly-rich IDRs seldom feature poly-Gly tracts. The protein fused in sarcoma (FUS) is an exception. This protein includes two 10-residue poly-Gly tracts within the prion-like domain (PLD) and at the interface between the PLD and the RNA binding domain. Poly-Gly tracts are known to be highly insoluble, being potent drivers of self-assembly into solid-like fibrils. Given that the internal concentrations of FUS and FUS-like molecules cross the high micromolar and even millimolar range within condensates, we reasoned that the intrinsic insolubility of poly-Gly tracts might be germane to emergent fluid-to-solid transitions within condensates. To assess this possibility, we characterized the concentration-dependent self-assembly for three non-overlapping 25-residue Gly-rich peptides derived from FUS. Two of the three peptides feature 10-residue poly-Gly tracts. These peptides form either long fibrils based on twisted ribbon-like structures or self-supporting gels based on physical cross-links of fibrils. Conversely, the peptide with similar Gly contents but lacking a poly-Gly tract does not form fibrils or gels. Instead, it remains soluble across a wide range of concentrations. Our findings highlight the ability of poly-Gly tracts within IDRs that drive phase separation to undergo self-assembly. We propose that these tracts are likely to contribute to nucleation of fibrillar solids within dense condensates formed by FUS.

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1021/acs.biochem.1c00501

Modeling uniquely human gene regulatory function via targeted humanization of the mouse genome

NOMIS Researcher(s)

Published in

November 2, 2021

The evolution of uniquely human traits likely entailed changes in developmental gene regulation. Human Accelerated Regions (HARs), which include transcriptional enhancers harboring a significant excess of human-specific sequence changes, are leading candidates for driving gene regulatory modifications in human development. However, insight into whether HARs alter the level, distribution, and timing of endogenous gene expression remains limited. We examined the role of the HAR HACNS1 (HAR2) in human evolution by interrogating its molecular functions in a genetically humanized mouse model. We find that HACNS1 maintains its human-specific enhancer activity in the mouse embryo and modifies expression of Gbx2, which encodes a transcription factor, during limb development. Using single-cell RNA-sequencing, we demonstrate that Gbx2 is upregulated in the limb chondrogenic mesenchyme of HACNS1 homozygous embryos, supporting that HACNS1 alters gene expression in cell types involved in skeletal patterning. Our findings illustrate that humanized mouse models provide mechanistic insight into how HARs modified gene expression in human evolution.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41467-021-27899-w

Colon cancer checks in when bile acids check out: The bile acid–nuclear receptor axis in colon cancer

NOMIS Researcher(s)

Published in

November 1, 2021

Bile acids (BAs) are a class of hepatically derived metabolite-hormones with prominent roles in nutrient absorption, metabolic and immune homeostasis in the intestine. BAs are ligands for multiple nuclear receptors (NRs), through which they confer transcriptional regulation on target genes that form an enterohepatic hormonal feedback loop to regulate BA synthesis and maintain lipid homeostasis. Endogenous BAs made by the host undergo significant biotransformation by the gut microbiota in the intestine, which diversifies the intestinal BA pool and facilitate host–microbiota cross-talk through BA-mediated signaling. BAs dysregulation contributes to development of metabolic diseases, pathological inflammation and colon cancer. This review provides a brief historic perspective of the study of NR-mediated BA signaling transduction, with a focus on recent advancements in understanding the active role the gut microbiome plays in reshaping intestinal BA landscape, and the implications of novel microbially derived BAs in modulating immune homeostasis and cancer development in the host. Targeting the BA–NR signaling axis for pharmacological intervention provides ample opportunities in the prevention and treatment of intestinal diseases.

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1042/EBC20210038

Load More