Systems Biology
Targeting YTHDF2/MDSCs to improve radiotherapy
Cell Chem Biol. 2023 Jul 20;30(7):703-705. doi: 10.1016/j.chembiol.2023.06.024.
ABSTRACT
Immunosuppression contributes to tumor-radiotherapy failure, but the mechanism remains elusive. Wang et al.1 reported that ionizing radiation (IR) induces YTHDF2 expression in myeloid-derived suppressor cells (MDSCs) via an IR-YTHDF2-NF-κB circuit, which contributes to MDSC expansion/migration and treatment failure. Genetic depletion or pharmacological inhibition of YTHDF2 overcomes immunosuppression and improves radiotherapy.
PMID:37478827 | DOI:10.1016/j.chembiol.2023.06.024
KRAS regulation of miRNA: Stepping on the brake to go faster
Mol Cell. 2023 Jul 20;83(14):2390-2392. doi: 10.1016/j.molcel.2023.06.029.
ABSTRACT
In this issue of Molecular Cell, Shui et al.1 use a systems biology approach to unravel a paradoxical role of microRNA in oncogenic KrasG12D regulation of gene and protein expression.
PMID:37478822 | DOI:10.1016/j.molcel.2023.06.029
UNMF: a unified nonnegative matrix factorization for multi-dimensional omics data
Brief Bioinform. 2023 Jul 21:bbad253. doi: 10.1093/bib/bbad253. Online ahead of print.
ABSTRACT
Factor analysis, ranging from principal component analysis to nonnegative matrix factorization, represents a foremost approach in analyzing multi-dimensional data to extract valuable patterns, and is increasingly being applied in the context of multi-dimensional omics datasets represented in tensor form. However, traditional analytical methods are heavily dependent on the format and structure of the data itself, and if these change even slightly, the analyst must change their data analysis strategy and techniques and spend a considerable amount of time on data preprocessing. Additionally, many traditional methods cannot be applied as-is in the presence of missing values in the data. We present a new statistical framework, unified nonnegative matrix factorization (UNMF), for finding informative patterns in messy biological data sets. UNMF is designed for tidy data format and structure, making data analysis easier and simplifying the development of data analysis tools. UNMF can handle a wide range of data structures and formats, and works seamlessly with tensor data including missing observations and repeated measurements. The usefulness of UNMF is demonstrated through its application to several multi-dimensional omics data, offering user-friendly and unified features for analysis and integration. Its application holds great potential for the life science community. UNMF is implemented with R and is available from GitHub (https://github.com/abikoushi/moltenNMF).
PMID:37478378 | DOI:10.1093/bib/bbad253
Extent of intraspecific trait variability in ecologically central and marginal populations of a dominant alpine plant across European mountains
Ann Bot. 2023 Jul 21:mcad105. doi: 10.1093/aob/mcad105. Online ahead of print.
ABSTRACT
BACKGROUND AND AIMS: Studying trait variability and restricted gene flow between populations species can reveal species dynamics. Peripheral populations commonly exhibit lower genetic diversity and trait variability due to isolation and ecological marginality, unlike central populations experiencing gene flow and optimal conditions. This study focused on Carex curvula, the dominant species in alpine acidic meadows of European mountains. The species is sparser in dry areas like the Pyrenees and Balkans, compared to the Central-Eastern Alps and Carpathians. We hypothesized that distinct population groups could be identified based on their mean functional trait values and their correlation with the environment; we predict that ecologically marginal populations would have stronger trait correlations, lower within-population trait variability (ITV), and lower genetic diversity than populations of optimal habitats.
METHODS: Sampling was conducted in 34 populations that spanned the entire distribution range of C. curvula. We used hierarchical clustering to identify emergent functional groups of populations, defined by combinations of multiple traits associated with nutrient economy and drought tolerance (e.g., specific leaf area, anatomy). We contrasted the geographic distribution of these groups in relation to environment and genetic structure. We compared pairwise trait relationships, within-population trait variation (ITV), and neutral genetic diversity between groups.
KEY RESULTS: Our study identified emergent functional groups of populations. Those in the southernmost ranges, specifically the Pyrenees and Balkan region, showed drought-tolerant trait syndromes and correlated with indicators of limited water availability. While we noted a decline in population genetic diversity, we did not observe any significant changes in ITV in ecologically marginal (peripheral) populations.
CONCLUSIONS: Our research exemplifies the relationship between ecological marginality and geographical peripherality, which in this case study is linked to genetic depauperation but not reduced ITV. Understanding these relationships is crucial for understanding the biogeographical factors shaping trait variation.
PMID:37478315 | DOI:10.1093/aob/mcad105
Development and characterization of mouse anti-canine PD-L1 monoclonal antibodies and their expression in canine tumors by immunohistochemistry <em>in vitro</em>
Vet Q. 2023 Jul 21:1-15. doi: 10.1080/01652176.2023.2240380. Online ahead of print.
ABSTRACT
Immune escape is the hallmark of carcinogenesis. This widely-known mechanism is the overexpression of immune checkpoint ligands, such as programmed cell death protein 1 and programmed death-ligand 1 (PD-1/PD-L1), leading to T cell anergy. Therefore, cancer immunotherapy with specific binding to these receptors has been developed to treat human cancers. Due to the lack of cross-reactivity of these antibodies in dogs, a specific canine PD-1/PD-L1 antibody is required. The aim of this study is to develop mouse anti-canine PD-L1 (cPD-L1) monoclonal antibodies and characterize their in vitro properties. Six mice were immunized with recombinant cPD-L1 with a fusion of human Fc tag. The hybridoma clones that successfully generated anti-cPD-L1 antibodies and had neutralizing activity were selected for monoclonal antibody production. Antibody properties were tested by immunosorbent assay, surface plasmon resonance, and immunohistochemistry. Four hybridomas were effectively bound and blocked to recombinant cPD-L1 and cPD-1-His-protein, respectively. Candidate mouse monoclonal antibodies worked efficiently on formalin-fixed paraffin-embedded tissues of canine cancers, including cutaneous T-cell lymphomas, mammary carcinomas, soft tissue sarcomas, squamous cell carcinomas, and malignant melanomas. However, functional assays of these anti-cPD-L1 antibodies need further investigation to prove their abilities as therapeutic drugs in dogs as well as their applications as prognostic markers.
PMID:37477617 | DOI:10.1080/01652176.2023.2240380
Transcriptome architecture of the three main lineages of agrobacteria
mSystems. 2023 Jul 21:e0033323. doi: 10.1128/msystems.00333-23. Online ahead of print.
ABSTRACT
Agrobacteria are a diverse, polyphyletic group of prokaryotes with multipartite genomes capable of transferring DNA into the genomes of host plants, making them an essential tool in plant biotechnology. Despite their utility in plant transformation, genome-wide transcriptional regulation is not well understood across the three main lineages of agrobacteria. Transcription start sites (TSSs) are a necessary component of gene expression and regulation. In this study, we used differential RNA-seq and a TSS identification algorithm optimized on manually annotated TSS, then validated with existing TSS to identify thousands of TSS with nucleotide resolution for representatives of each lineage. We extend upon the 356 TSSs previously reported in Agrobacterium fabrum C58 by identifying 1,916 TSSs. In addition, we completed genomes and phenotyping of Rhizobium rhizogenes C16/80 and Allorhizobium vitis T60/94, identifying 2,650 and 2,432 TSSs, respectively. Parameter optimization was crucial for an accurate, high-resolution view of genome and transcriptional dynamics, highlighting the importance of algorithm optimization in genome-wide TSS identification and genomics at large. The optimized algorithm reduced the number of TSSs identified internal and antisense to the coding sequence on average by 90.5% and 91.9%, respectively. Comparison of TSS conservation between orthologs of the three lineages revealed differences in cell cycle regulation of ctrA as well as divergence of transcriptional regulation of chemotaxis-related genes when grown in conditions that simulate the plant environment. These results provide a framework to elucidate the mechanistic basis and evolution of pathology across the three main lineages of agrobacteria. IMPORTANCE Transcription start sites (TSSs) are fundamental for understanding gene expression and regulation. Agrobacteria, a group of prokaryotes with the ability to transfer DNA into the genomes of host plants, are widely used in plant biotechnology. However, the genome-wide transcriptional regulation of agrobacteria is not well understood, especially in less-studied lineages. Differential RNA-seq and an optimized algorithm enabled identification of thousands of TSSs with nucleotide resolution for representatives of each lineage. The results of this study provide a framework for elucidating the mechanistic basis and evolution of pathology across the three main lineages of agrobacteria. The optimized algorithm also highlights the importance of parameter optimization in genome-wide TSS identification and genomics at large.
PMID:37477440 | DOI:10.1128/msystems.00333-23
The US21 viroporin of human cytomegalovirus stimulates cell migration and adhesion
mBio. 2023 Jul 21:e0074923. doi: 10.1128/mbio.00749-23. Online ahead of print.
ABSTRACT
The human cytomegalovirus (HCMV) US12 gene family contributes to virus-host interactions by regulating the virus' cell tropism and its evasion of host innate immune responses. US21, one of the 10 US12 genes (US12-US21), is a descendant of a captured cellular transmembrane BAX inhibitor motif-containing gene. It encodes a 7TMD endoplasmic reticulum (ER)-resident viroporin (pUS21) capable of reducing the Ca2+ content of ER stores, which, in turn, protects cells against apoptosis. Since regulation of Ca2+ homeostasis affects a broad range of cellular responses, including cell motility, we investigated whether pUS21 might also interfere with this cytobiological consequence of Ca2+ signaling. Indeed, deletion of the US21 gene impaired the ability of HCMV-infected cells to migrate, whereas expression of US21 protein stimulated cell migration and adhesion, as well as focal adhesion (FA) dynamics, in a way that depended on its ability to manipulate ER Ca2+ content. Mechanistic studies revealed pUS21-mediated cell migration to involve calpain 2 activation since its inhibition prevented the viroporin's effects on cell motility. Pertinently, pUS21 expression stimulated a store-operated Ca2+ entry (SOCE) mechanism that may determine the activation of calpain 2 by promoting Ca2+ entry. Furthermore, pUS21 was observed to interact with talin-1, a calpain 2 substrate, and crucial protein component of FA complexes. A functional consequence of this interaction was confirmed by talin-1 knockdown, which abrogated the pUS21-mediated increase in cell migration. Together, these results indicate the US21-encoded viroporin to be a viral regulator of cell adhesion and migration in the context of HCMV infection. IMPORTANCE Human cytomegalovirus (HCMV) is an opportunistic pathogen that owes part of its success to the capture, duplication, and tuning of cellular genes to generate modern viral proteins which promote infection and persistence in the host by interfering with many cell biochemical and physiological pathways. The US21 viral protein provides an example of this evolutionary strategy: it is a cellular-derived calcium channel that manipulates intracellular calcium homeostasis to confer edges to HCMV replication. Here, we report on the characterization of a novel function of the US21 protein as a viral regulator of cell migration and adhesion through mechanisms involving its calcium channel activity. Characterization of HCMV multifunctional regulatory proteins, like US21, supports the better understanding of viral pathogenesis and may open avenues for the design of new antiviral strategies that exploit their functions.
PMID:37477430 | DOI:10.1128/mbio.00749-23
Conjugation of Vancomycin with a Single Arginine Improves Efficacy against Mycobacteria by More Effective Peptidoglycan Targeting
J Med Chem. 2023 Jul 21. doi: 10.1021/acs.jmedchem.3c00565. Online ahead of print.
ABSTRACT
Drug resistant bacterial infections have emerged as one of the greatest threats to public health. The discovery and development of new antimicrobials and anti-infective strategies are urgently needed to address this challenge. Vancomycin is one of the most important antibiotics for the treatment of Gram-positive infections. Here, we introduce the vancomycin-arginine conjugate (V-R) as a highly effective antimicrobial against actively growing mycobacteria and difficult-to-treat mycobacterial biofilm populations. Further improvement in efficacy through combination treatment of V-R to inhibit peptidoglycan synthesis and ethambutol to inhibit arabinogalactan synthesis underscores the ability to identify compound synergies to more effectively target the Achilles heel of the cell-wall assembly. Moreover, we introduce mechanistic activity data and a molecular model derived from a d-Ala-d-Ala-bound vancomycin structure that we hypothesize underlies the molecular basis for the antibacterial improvement attributed to the arginine modification that is specific to peptidoglycan chemistry employed by mycobacteria and distinct from Gram-positive pathogens.
PMID:37477249 | DOI:10.1021/acs.jmedchem.3c00565
System-wide optimization of an orthogonal translation system with enhanced biological tolerance
Mol Syst Biol. 2023 Jul 21:e10591. doi: 10.15252/msb.202110591. Online ahead of print.
ABSTRACT
Over the past two decades, synthetic biological systems have revolutionized the study of cellular physiology. The ability to site-specifically incorporate biologically relevant non-standard amino acids using orthogonal translation systems (OTSs) has proven particularly useful, providing unparalleled access to cellular mechanisms modulated by post-translational modifications, such as protein phosphorylation. However, despite significant advances in OTS design and function, the systems-level biology of OTS development and utilization remains underexplored. In this study, we employ a phosphoserine OTS (pSerOTS) as a model to systematically investigate global interactions between OTS components and the cellular environment, aiming to improve OTS performance. Based on this analysis, we design OTS variants to enhance orthogonality by minimizing host process interactions and reducing stress response activation. Our findings advance understanding of system-wide OTS:host interactions, enabling informed design practices that circumvent deleterious interactions with host physiology while improving OTS performance and stability. Furthermore, our study emphasizes the importance of establishing a pipeline for systematically profiling OTS:host interactions to enhance orthogonality and mitigate mechanisms underlying OTS-mediated host toxicity.
PMID:37477096 | DOI:10.15252/msb.202110591
Race-specific genotypes of <em>Pseudomonas syringae</em> pv. tomato are defined by the presence of mobile DNA elements within the genome
Front Plant Sci. 2023 Jul 5;14:1197706. doi: 10.3389/fpls.2023.1197706. eCollection 2023.
ABSTRACT
Pseudomonas syringae pv. tomato is the causal agent of bacterial speck of tomato, an important disease that results in severe crop production losses worldwide. Currently, two races within phylogroup 01a (PG01a) are described for this pathogen. Race 0 strains have avirulence genes for the expression of type III system-associated effectors AvrPto1 and AvrPtoB, that are recognized and targeted by the effector-triggered immunity in tomato cultivars having the pto race-specific resistance gene. Race 1 strains instead lack the avrPto1 and avrPtoB genes and are therefore capable to aggressively attack all tomato cultivars. Here, we have performed the complete genome sequencing and the analysis of P. syringae pv. tomato strain DAPP-PG 215, which was described as a race 0 strain in 1996. Our analysis revealed that its genome comprises a 6.2 Mb circular chromosome and two plasmids (107 kb and 81 kb). The results indicate that the strain is phylogenetically closely related to strains Max13, K40, T1 and NYS-T1, all known race 1 strains. The chromosome of DAPP-PG 215 encodes race 1-associated genes like avrA and hopW1 and lacks race 0-associated genes like hopN1, giving it a race 1 genetic background. However, the genome harbors a complete ortholog of avrPto1, which allows the strain to display a race 0 phenotype. Comparative genomics with several PG01a genomes revealed that mobile DNA elements are rather involved in the evolution of the two different races.
PMID:37476164 | PMC:PMC10354423 | DOI:10.3389/fpls.2023.1197706
From omics to Cellular mechanisms in mammalian cell factory development
Curr Opin Chem Eng. 2021 Jun;32:100688. doi: 10.1016/j.coche.2021.100688. Epub 2021 May 26.
ABSTRACT
Mammalian cells have been used widely as biopharmaceutical cell factories due to their ability to make complex biotherapeutic proteins with human-compatible modifications. However, their application for some products has been hampered by low protein yields. Numerous studies have aimed to characterize cellular bottlenecks in the hope of boosting protein productivity, but the complexity of the underlying pathways and the diversity of the modifications have complicated cell engineering when relying solely on traditional methodologies. Incorporating omics-based and systems approaches into cell engineering can provide valuable insights into desirable phenotypes of cell factories. Here, we discuss cell engineering strategies for enhancing protein productivity in mammalian cell factories, particularly CHO and HEK293, and the opportunities and limitations of the genome-wide screening and multi-omics approaches for guiding cell engineering. Systems biology strategies will also be discussed to show how they refine our understanding of the cellular mechanisms which will aid in effective engineering strategies.
PMID:37475722 | PMC:PMC10357924 | DOI:10.1016/j.coche.2021.100688
Effects of pejus and pessimum zone salinity stress on gill proteome networks and energy homeostasis in Oreochromis mossambicus
Proteomics. 2023 Jul 20:e2300121. doi: 10.1002/pmic.202300121. Online ahead of print.
ABSTRACT
Salinity tolerance in fish involves a suite of physiological changes, but a cohesive theory leading to a mechanistic understanding at the organismal level is lacking. To examine the potential of adapting energy homeostasis theory in the context of salinity stress in teleost fish, Oreochromis mossambicus were acclimated to hypersalinity at multiple rates and durations to determine salinity ranges of tolerance and resistance. Over 3000 proteins were quantified simultaneously to analyze molecular phenotypes associated with hypersalinity. A species- and tissue-specific data-independent acquisition (DIA) assay library of MSMS spectra was created. Protein networks representing complex molecular phenotypes associated with salinity acclimation were generated. O. mossambicus has a wide "zone of resistance" from 75 g/kg salinity to 120 g/kg. Crossing into the zone of resistance resulted in marked phenotypic changes including blood osmolality over 400 mOsm/kg, reduced body condition, and cessation of feeding. Protein networks impacted by hypersalinity consist of electron transport chain (ETC) proteins and specific osmoregulatory proteins. Cytoskeletal, cell adhesion, and extracellular matrix proteins are enriched in networks that are sensitive to the critical salinity threshold. These network analyses identify specific proteome changes that are associated with distinct zones described by energy homeostasis theory and distinguish them from general hypersalinity-induced proteome changes.
PMID:37475512 | DOI:10.1002/pmic.202300121
Transplantation of gut microbiota from old mice into young healthy mice reduces lean mass but not bone mass
Gut Microbes. 2023 Jan-Dec;15(1):2236755. doi: 10.1080/19490976.2023.2236755.
ABSTRACT
Aging is associated with low bone and lean mass as well as alterations in the gut microbiota (GM). In this study, we determined whether the reduced bone mass and relative lean mass observed in old mice could be transferred to healthy young mice by GM transplantation (GMT). GM from old (21-month-old) and young adult (5-month-old) donors was used to colonize germ-free (GF) mice in three separate studies involving still growing 5- or 11-week-old recipients and 17-week-old recipients with minimal bone growth. The GM of the recipient mice was similar to that of the donors, demonstrating successful GMT. GM from old mice did not have statistically significant effects on bone mass or bone strength, but significantly reduced the lean mass percentage of still growing recipient mice when compared with recipients of GM from young adult mice. The levels of propionate in the cecum of mice receiving old donor GM were significantly lower than those in mice receiving young adult donor GM. Bacteroides ovatus was enriched in the microbiota of recipient mice harboring GM from young adult donors. The presence of B. ovatus was not only significantly associated with high lean mass percentage in mice, but also with lean mass adjusted for fat mass in the large human HUNT cohort. In conclusion, GM from old mice reduces lean mass percentage but not bone mass in young, healthy, still growing recipient mice. Future studies are warranted to determine whether GM from young mice improves the musculoskeletal phenotype of frail elderly recipient mice.
PMID:37475479 | DOI:10.1080/19490976.2023.2236755
A two-protein cocktail elicits a protective immune response against Acinetobacter baumannii in a murine infection model
Microb Pathog. 2023 Jul 18:106262. doi: 10.1016/j.micpath.2023.106262. Online ahead of print.
ABSTRACT
PURPOSE: Due to its high drug resistance, Acinetobacter baumannii is a priority for new therapeutic measures like vaccines. In this study, the protectivity of a combination cocktail of Omp34 and BauA as a vaccine against A. baumannii was studied in a murine sepsis model.
METHODS: The antibody titers were raised to Omp34 and BauA in BALB/c mice and assessed by indirect ELISA. The immunized mice were challenged with A. baumannii ATCC 19606. The bacterial loads in the liver, spleen, and lungs were also determined.
RESULTS: A significant increase in survival of the immunized mice was noted. In active immunity, the survival rates in mice receiving Omp34 and BauA alone or in combination were 100%. A significant decrease in the bacterial load was observed in the spleens, livers, and lungs of vaccinated mice. Anti-BauA and anti-Omp34 sera crossly detected Omp34 and BauA respectively. The decrease in bacterial load in body organs of mice vaccinated with a combination of the two proteins was significantly higher than those of the single proteins in both actively and passively immunized mice. In passive immunity, the survival rate of mice receiving specific sera raised to the combination of these proteins was 85.7%.
CONCLUSION: Higher protection by a combination of Omp34 and BauA than Omp34 or BauA could be attributed to targeting simultaneously both surface antigens indicating the synergistic effect of Omp34 and BauA as suitable vaccine candidates in the prevention or treatment of A. baumannii infections.
PMID:37474079 | DOI:10.1016/j.micpath.2023.106262
Endogenous anti-tumorigenic nitro-fatty acids inhibit the ubiquitin-proteasome system by directly targeting the 26S proteasome
Cell Chem Biol. 2023 Jul 6:S2451-9456(23)00195-2. doi: 10.1016/j.chembiol.2023.06.017. Online ahead of print.
ABSTRACT
Nitro-fatty acids (NFAs) are endogenous lipid mediators causing a spectrum of anti-inflammatory effects by covalent modification of key proteins within inflammatory signaling pathways. Recent animal models of solid tumors have helped demonstrate their potential as anti-tumorigenic therapeutics. This study evaluated the anti-tumorigenic effects of NFAs in colon carcinoma cells and other solid and leukemic tumor cell lines. NFAs inhibited the ubiquitin-proteasome system (UPS) by directly targeting the 26S proteasome, leading to polyubiquitination and inhibition of the proteasome activities. UPS suppression induced the unfolded protein response, resulting in tumor cell death. The NFA-mediated effects were substantial, specific, and enduring, representing a unique mode of action for UPS suppression. This study provides mechanistic insights into the biological actions of NFAs as possible endogenous tumor-suppressive factors, indicating that NFAs might be key structures for designing a novel class of direct proteasome inhibitors.
PMID:37473760 | DOI:10.1016/j.chembiol.2023.06.017
BayesTME: An end-to-end method for multiscale spatial transcriptional profiling of the tissue microenvironment
Cell Syst. 2023 Jul 19;14(7):605-619.e7. doi: 10.1016/j.cels.2023.06.003.
ABSTRACT
Spatial variation in cellular phenotypes underlies heterogeneity in immune recognition and response to therapy in cancer and many other diseases. Spatial transcriptomics holds the potential to quantify such variation, but existing analysis methods are limited by their focus on individual tasks such as spot deconvolution. We present BayesTME, an end-to-end Bayesian method for analyzing spatial transcriptomics data. BayesTME unifies several previously distinct analysis goals under a single, holistic generative model. This unified approach enables BayesTME to deconvolve spots into cell phenotypes without any need for paired single-cell RNA-seq. BayesTME then goes beyond spot deconvolution to uncover spatial expression patterns among coordinated subsets of genes within phenotypes, which we term spatial transcriptional programs. BayesTME achieves state-of-the-art performance across myriad benchmarks. On human and zebrafish melanoma tissues, BayesTME identifies spatial transcriptional programs that capture fundamental biological phenomena such as bilateral symmetry and tumor-associated fibroblast and macrophage reprogramming. BayesTME is open source.
PMID:37473731 | DOI:10.1016/j.cels.2023.06.003
Biphasic JNK-Erk signaling separates the induction and maintenance of cell senescence after DNA damage induced by topoisomerase II inhibition
Cell Syst. 2023 Jul 19;14(7):582-604.e10. doi: 10.1016/j.cels.2023.06.005.
ABSTRACT
Genotoxic stress in mammalian cells, including those caused by anti-cancer chemotherapy, can induce temporary cell-cycle arrest, DNA damage-induced senescence (DDIS), or apoptotic cell death. Despite obvious clinical importance, it is unclear how the signals emerging from DNA damage are integrated together with other cellular signaling pathways monitoring the cell's environment and/or internal state to control different cell fates. Using single-cell-based signaling measurements combined with tensor partial least square regression (t-PLSR)/principal component analysis (PCA) analysis, we show that JNK and Erk MAPK signaling regulates the initiation of cell senescence through the transcription factor AP-1 at early times after doxorubicin-induced DNA damage and the senescence-associated secretory phenotype (SASP) at late times after damage. These results identify temporally distinct roles for signaling pathways beyond the classic DNA damage response (DDR) that control the cell senescence decision and modulate the tumor microenvironment and reveal fundamental similarities between signaling pathways responsible for oncogene-induced senescence (OIS) and senescence caused by topoisomerase II inhibition. A record of this paper's transparent peer review process is included in the supplemental information.
PMID:37473730 | DOI:10.1016/j.cels.2023.06.005
Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape
Cell Syst. 2023 Jul 19;14(7):551-562.e5. doi: 10.1016/j.cels.2023.06.001.
ABSTRACT
The integrated stress response (ISR) is a conserved signaling network that detects aberrations and computes cellular responses. Dissecting these computations has been difficult because physical and chemical inducers of stress activate multiple parallel pathways. To overcome this challenge, we engineered a photo-switchable control over the ISR sensor kinase PKR (opto-PKR), enabling virtual, on-target activation. Using light to control opto-PKR dynamics, we traced information flow through the transcriptome and for key downstream ISR effectors. Our analyses revealed a biphasic, proportional transcriptional response with two dynamic modes, transient and gradual, that correspond to adaptive and terminal outcomes. We then constructed an ordinary differential equation (ODE) model of the ISR, which demonstrated the dependence of future stress responses on past stress. Finally, we tested our model using high-throughput light-delivery to map the stress memory landscape. Our results demonstrate that cells encode information in stress levels, durations, and the timing between encounters. A record of this paper's transparent peer review process is included in the supplemental information.
PMID:37473728 | DOI:10.1016/j.cels.2023.06.001
LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits
Nat Aging. 2023 Jul 20. doi: 10.1038/s43587-023-00464-4. Online ahead of print.
ABSTRACT
Protein misfolding is a major factor of neurodegenerative diseases. Post-mitotic neurons are highly susceptible to protein aggregates that are not diluted by mitosis. Therefore, post-mitotic cells may have a specific protein quality control system. Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons. LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins. Lonrf2-/- mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia. Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture. The shortening of neurites in MNs from patients with amyotrophic lateral sclerosis is rescued by ectopic expression of LONRF2. Our findings reveal that LONRF2 is a protein quality control ligase whose loss may contribute to MN degeneration and motor deficits.
PMID:37474791 | DOI:10.1038/s43587-023-00464-4
Nicotinamide mononucleotide (NMN) alleviates the poly(I:C)-induced inflammatory response in human primary cell cultures
Sci Rep. 2023 Jul 20;13(1):11765. doi: 10.1038/s41598-023-38762-x.
ABSTRACT
NMN is the direct precursor of nicotinamide adenine dinucleotide (NAD+) and is considered as a key factor for increasing NAD+ levels and mitochondrial activity in cells. In this study, based on transcriptome analysis, we showed that NMN alleviates the poly(I:C)-induced inflammatory response in cultures of two types of human primary cells, human pulmonary microvascular endothelial cells (HPMECs) and human coronary artery endothelial cells (HCAECs). Major inflammatory mediators, including IL6 and PARP family members, were grouped into coexpressed gene modules and significantly downregulated under NMN exposure in poly(I:C)-activated conditions in both cell types. The Bayesian network analysis of module hub genes predicted common genes, including eukaryotic translation initiation factor 4B (EIF4B), and distinct genes, such as platelet-derived growth factor binding molecules, in HCAECs, which potentially regulate the identified inflammation modules. These results suggest a robust regulatory mechanism by which NMN alleviates inflammatory pathway activation, which may open up the possibility of a new role for NMN replenishment in the treatment of chronic or acute inflammation.
PMID:37474783 | DOI:10.1038/s41598-023-38762-x