Barone M, Peidli S, Neuschulz A
… +13 more, Riesterer K, Iwert C, Junquera L, Sai S, Bolaji O, Bakoueva D, Appelt C, Obermayer B, Klinger B, Trinks A, Sieber A, Blüthgen N, Sawitzki B
Memory-like or precursor exhausted (Tpex) CD8 T cells are a critical reservoir in chronic infections and cancer, yet the signals sustaining their cytokine production remain unclear. Here, we identify KLRF1 as part of a C...Memory-like or precursor exhausted (Tpex) CD8 T cells are a critical reservoir in chronic infections and cancer, yet the signals sustaining their cytokine production remain unclear. Here, we identify KLRF1 as part of a CD4-CD8 communication axis that supports cytokine production in late-differentiated human CD8 T cells. KLRF1 is upregulated in late-differentiated CD8 T cells, and neutralizing KLRF1 reduces TNF and IFN-γ production. Differentiated CD4 T cells express the KLRF1 ligand AICL, and in co-culture only AICL - not AICL⁻ - CD4 T cells enhance cytokine output in CD8 T cells. Using spatial proteomics of lung adenocarcinoma and adjacent tissue, we found that CD4 AICL and CD8 KLRF1 T cells are enriched and spatially interacting in non-tumor regions, whereas both populations are reduced within tumor tissue. Single-cell RNA-seq of tissue samples and scRNA/ATAC analyses of circulating immune cells further showed that CD8KLRF1 T cells display a Tpex-like transcriptional and chromatin-accessibility profile. Together, these data identify the AICL-KLRF1 axis as a CD4-CD8 communication pathway that supports cytokine competence in late-differentiated CD8 T cells.
The social behaviors of microbes provide unique opportunities for testing social evolution theories. How can altruistic behaviors arise by natural selection is a central challenge in biology. Green-beard effect has been...The social behaviors of microbes provide unique opportunities for testing social evolution theories. How can altruistic behaviors arise by natural selection is a central challenge in biology. Green-beard effect has been proposed as a basic mechanism for the evolution of altruistic behaviors. Yet, green-beard genes are generally thought to be rare. Here, we find that the Schizosaccharomyces pombe gsf2 gene mediates flocculation-like aggregation, and flocculation is triggered by acid stresses. gsf2-expressing cells preferentially adhere to each other. The expression of gsf2 is costly, but gsf2-expressing cells preferentially adhere to each other and protect each other from external stress. Gsf2 is highly variable in natural populations, likely contributing to different flocculation intensity. These findings suggest that gsf2 is a gradient green-beard gene that drives the altruism among gsf2 carriers. Moreover, we find that gsf2 is a new gene that originated very recently. Our results provide insights into the origin and evolution of green-beard genes.
Unfairly labeled as ‘snot’ or ‘phlegm’ mucus is a biological marvel that plays a crucial role in protecting the body from pathogens and pollutants. Its multiple functions and extraordinary properties have inspired new bi...Unfairly labeled as ‘snot’ or ‘phlegm’ mucus is a biological marvel that plays a crucial role in protecting the body from pathogens and pollutants. Its multiple functions and extraordinary properties have inspired new biomaterials. [Image: see text]
Garcia-Peterson LM, Wellman AS, Xu X
… +13 more, Ji M, Duval C, Shats I, Wu X, Randall TA, Bostan H, Cunefare D, Ganta CK, Sifre M, Xu X, Blumberg RS, Li JL, Li X
Paneth cells, intestine-originated innate immune-like cells, are important for maintenance of the intestinal stem cell niche, gut microbiota, and gastrointestinal barrier. Dysfunctional Paneth cells under pathological co...Paneth cells, intestine-originated innate immune-like cells, are important for maintenance of the intestinal stem cell niche, gut microbiota, and gastrointestinal barrier. Dysfunctional Paneth cells under pathological conditions are a site of origin for intestinal inflammation. However, mechanisms underlying stress-induced Paneth cell dysregulation remain unclear. Here, we report that SIRT1, the most conserved mammalian NAD-dependent protein deacetylase and a well-known genetic repressor of inflammation, cell-autonomously suppresses Paneth cell function and sensitizes the gut epithelium to environmental stress. Specifically, deletion of Paneth cell SIRT1 in mice elevates Wnt signaling and ATF4/endoplasmic reticulum stress pathway in Paneth cells. These molecular alterations are coupled with increased Paneth cell abundance and enhanced anti-microbial peptide production in young mice, improved protection against intestinal immune cell expansion in aged mice, and increased resistance to chemically induced colitis. Using microbiota-depleted mice with or without fecal transplantation, we further demonstrate that Paneth cell SIRT1 deficiency ameliorates colitis by interacting with the gut microbiota. Collectively, our findings uncover an unanticipated function of Paneth cell SIRT1 in conferring stress sensitivity in the gut epithelium.
Shrama A, Zi Y, Pandit AS
… +16 more, Jha K, Sinha VK, Nagesh D, Shivanaiah B, Ravi V, Ghosh S, Khan D, Prabhashankar AB, Sumi TS, Rajpurohit S, Ningaraju S, Raghu S, Srivastava A, Singh M, Lin H, Sundaresan NR
Increased global protein synthesis is associated with the development and progression of several aging-related diseases and disorders. Strategies like calorie restriction and pharmacological inhibition of protein synthes...Increased global protein synthesis is associated with the development and progression of several aging-related diseases and disorders. Strategies like calorie restriction and pharmacological inhibition of protein synthesis have exhibited health-promoting effects. However, the complex molecular events that regulate global protein synthesis are not completely understood. Here, we report that SIRT2, a histone deacetylase, negatively regulates global protein synthesis by inhibiting the mTORC1 pathway via deacetylating Rheb and promoting its degradation. Our in vitro results suggest that SIRT2 deficiency increases protein synthesis, whereas SIRT2 overexpression suppresses protein synthesis. SIRT2-deficient mice exhibit increased global protein synthesis in the hearts, which may contribute to the development of cardiac hypertrophy. Conversely, cardiac-specific overexpression reduces global protein synthesis in the hearts of SIRT2 transgenic mice. Mechanistically, SIRT2 binds to and deacetylates Rheb at K151 residue to enhance ubiquitin-proteosome-mediated degradation of Rheb. Depletion of Rheb rescues increased protein synthesis in SIRT2-inhibited conditions. Our findings suggest that SIRT2 activation could be a potential therapeutic strategy for treating diseases associated with increased protein synthesis.
RECQL4, a RecQ family helicase, is essential for DNA replication and genome stability. Mutations in RECQL4 cause severe human disorders yet we do not fully understand its functions, particularly regarding ATP-dependent h...RECQL4, a RecQ family helicase, is essential for DNA replication and genome stability. Mutations in RECQL4 cause severe human disorders yet we do not fully understand its functions, particularly regarding ATP-dependent helicase activity. To understand RECQL4's functions further, we performed a genome-wide forward genetic screen using a murine model harbouring patient-like RECQL4 mutations. We identify KLHDC3, a substrate-binding subunit of the Cullin-RING ligase E3 complex, loss as the most significant rescue allele. KLHDC3 loss restores proliferation and replication in RECQL4-deficient cells by stabilizing trace levels of a truncated RECQL4 fragment containing the N-terminal 480 amino acids, lacking the helicase and C-terminal regions. This RECQL4 fragment forms after Cre-mediated recombination of the Recql4 allele and contains a neo-degron sequence specific for KLHDC3. Although this mechanism does not apply to human mutations, it demonstrates that minimal RECQL4 levels, without any ATPase domain/activity, are sufficient to support DNA replication. This demonstrates that RECQL4 is an essential and non-redundant regulator of DNA replication and cell viability and that this activity does not require its ATP-dependent helicase activity.
The diversity of microbes reflects how cells adapt, interact and evolve across diverse environmental contexts and represents an unparalleled resource for training biological AI models. This microbial diversity can suppor...The diversity of microbes reflects how cells adapt, interact and evolve across diverse environmental contexts and represents an unparalleled resource for training biological AI models. This microbial diversity can support models that go beyond sequence to capture and design biological function across systems. [Image: see text]
Glial cells are crucial for nervous system development and function by clearing debris, protecting neurons and ensuring neuronal survival. In Drosophila, glia form the blood-brain barrier, which regulates neural stem cel...Glial cells are crucial for nervous system development and function by clearing debris, protecting neurons and ensuring neuronal survival. In Drosophila, glia form the blood-brain barrier, which regulates neural stem cell proliferation and shields the nervous system while maintaining communication with the rest of the organism. To uncover glial-specific roles, we here compare their transcriptome with that of neurons and macrophages. Our study identifies NimA, an uncharacterized member of the Nimrod family, as a glial-specific protein expressed during development. Unlike other family members (i.e. NimC1, Draper and NimC4/Simu) NimA is not involved in phagocytosis. Instead, NimA regulates cell-cell adhesion, crucial for maintaining the tight septate junctions of the larval BBB. Loss of NimA in BBB-forming glia compromises barrier integrity. Moreover, loss of NimA in those glia, or in glia that serve as neural stem cell niche, delays development, reduces brain size, impairs proliferation and reduces the neural stem cell pool. The identification of the glial-specific molecular landscape, including novel molecular players such as NimA, is key for understanding the contribution of glia to the nervous system.
Microglia maintain brain homeostasis via iC3b-mediated synaptic pruning. The Arp2/3 complex has been implicated in iC3b-mediated macrophage phagocytosis, but it is unclear whether it is similarly required in microglia in...Microglia maintain brain homeostasis via iC3b-mediated synaptic pruning. The Arp2/3 complex has been implicated in iC3b-mediated macrophage phagocytosis, but it is unclear whether it is similarly required in microglia in the CNS. We examined the question of CR3-dependent clearance of iC3b in microglia using a combination of in vitro and in situ physical confinement studies. Arp2/3 inhibition decreased iC3b phagocytosis and cell motility in vitro. Furthermore, microglia-like cells remove immobilized iC3b from the substrate in an Arp2/3-dependent fashion, in a process reminiscent of trogocytic synaptic pruning. We also used a novel approach to immobilize an iC3b gradient onto a substrate and demonstrate Arp2/3-dependent haptotactic migration toward increasing iC3b concentrations. While Arp2/3-deficient microglia robustly respond to ATP via chemotaxis within mouse hippocampal slices, they demonstrate a persistent inability to stably interact with iC3b-coated beads. The present study establishes new approaches to systematically interrogate molecular pathways relevant to synaptic pruning, advances the understanding of iC3b phagocytosis as a haptotactic response, and confirms that the Arp2/3-dependent haptotactic response is important for microglia function in the CNS microenvironment.
Microglial dynamics and homeostasis are crucial for maintaining central nervous system (CNS) function. To fulfill their homeostatic functions, microglia develop into ramified cells with highly dynamic cell protrusions. H...Microglial dynamics and homeostasis are crucial for maintaining central nervous system (CNS) function. To fulfill their homeostatic functions, microglia develop into ramified cells with highly dynamic cell protrusions. However, the detailed mechanisms underlying this developmental transition are largely unknown. Here, we investigate the role of the Actin-related protein 2/3 (Arp2/3) complex, a critical actin nucleator that controls the formation of actin branches, for the biology of tissue-resident microglia. By conditionally targeting Arpc4 in mice, we show that Arp2/3 depletion in tissue-resident microglia causes phenotypes beyond previously reported functions in other immune cell types. Our results identify an important role of Arp2/3 for controlling the developmental transition of microglia into cells with ramified morphology, homeostatic gene profile, and surveillance function in the CNS. Together, our results link actin remodeling to microglial maturation and activation, highlighting the Arp2/3 complex as a critical factor for maintaining the plasticity and preventing pathological activation of endogenous microglia.
A survey of researchers who compared AI-generated scientific reviews with journal-agnostic human peer review reveals that they overwhelmingly prefer using AI as a self-checking tool before submission rather than as a rep...A survey of researchers who compared AI-generated scientific reviews with journal-agnostic human peer review reveals that they overwhelmingly prefer using AI as a self-checking tool before submission rather than as a replacement for human reviewers. It encourages an “author-centric” model in which AI helps researchers improve their manuscripts before they are reviewed by their peers.
The immune checkpoint molecule, programmed cell death 1 (PD-1), critically regulates T-cell activation upon binding PD-L1 or PD-L2, making it a key target in cancer immunotherapy. Although extensively studied, the molecu...The immune checkpoint molecule, programmed cell death 1 (PD-1), critically regulates T-cell activation upon binding PD-L1 or PD-L2, making it a key target in cancer immunotherapy. Although extensively studied, the molecular mechanism of the inhibitory function of PD-1 remains incompletely understood. Using the biomembrane force probe (BFP), we measure catch-slip bond behavior between PD-1 and PD-L1/PD-L2 under force. Steered molecular dynamics (SMD) simulation reveals a force-induced bound state distinct from the force-free state observed in solved complex structures. Disrupting interactions that stabilize either state weakens the catch bond, and diminishes the inhibitory function of PD-1. Interestingly, soluble forms of PD-L1/PD-L2 compete with their surface-bound counterparts and attenuate PD-1-mediated T-cell inhibition, suggesting that soluble PD-1 ligands could potentially serve as anti-PD-1 drugs. Tumor growth studies using a gain of function mutant based on the catch-bond mechanism confirm the anti-cancer activity of soluble PD-L1. Our findings highlight that mechanical force governs the inhibitory function of PD-1 and suggest that PD-1 acts as a mechanical sensor in T-cell suppression. Thus, mechanical regulation should be considered when designing PD-1 blocking therapies.
Maternal effect genes (MEGs) produce factors that accumulate in oocytes and play critical roles in embryo development. Mutations of MEGs are frequently linked to reproductive and congenital disorders. The majority of ide...Maternal effect genes (MEGs) produce factors that accumulate in oocytes and play critical roles in embryo development. Mutations of MEGs are frequently linked to reproductive and congenital disorders. The majority of identified mammalian MEGs encode epigenetic factors and RNA regulators. Here, we identify a MEG encoding the transcription factor Thanatos-associated protein 1 (Thap1). Thap1 is highly expressed in mouse oocytes and early embryos. Oocyte-specific deletion of Thap1 results in delayed progression of mouse embryos from the 1-cell to the 2-cell stage and 1-2-cell arrest, accompanied by defective zygotic genome activation (ZGA) and strongly impaired female fertility. Mechanistically, THAP1 activates a critical subset of genes in oocytes, including Rrm1, which produces ribonucleotide reductase required for generating deoxynucleotide triphosphates (dNTPs). Low-input metabolome profiling across 7 stages during the oocyte-to-embryo transition shows gradual, THAP1-dependent dNTP accumulation that peaks in MII oocytes. Overexpression of Rrm1 in zygotes almost fully restores the 2-cell progression and ZGA in Thap1 maternal-knockout embryos. Our findings identify THAP1 as a key maternal effector critical for the earliest stage of mammalian development.
Regulation of RNA polymerase II (Pol II) transcription is closely associated with cell proliferation. However, it remains unclear how the Pol II transcription program is rewired in cancer to promote uncontrolled growth....Regulation of RNA polymerase II (Pol II) transcription is closely associated with cell proliferation. However, it remains unclear how the Pol II transcription program is rewired in cancer to promote uncontrolled growth. Here, we find that expression of NELFCD, a known negative transcription elongation factor, is upregulated in colorectal tumors. Auxin-dependent protein degradation of NELF-C in combination with nascent transcript sequencing demonstrates a direct role of NELF-C on Pol II transcription in this cancer. Strikingly, we demonstrate that the acute loss of NELF-C protein globally redistributes termination factors and perturbs Pol II transcription termination. These changes drive pervasive Pol II transcription into DNA replication zones, leading to transcription-replication conflict that may block the cell cycle in G1 or early S phase. Our findings reveal a previously unrecognized role of NELF in transcription termination and highlight NELF as a potential therapeutic target in colorectal cancer.
Artes MH, Iacobucci S, Barallobre MJ
… +14 more, Carballeira P, Garcia-Cajide M, Pérez-Venteo A, Padilla N, Viegas BS, Díaz-Vásquez A, Nacht AS, Vicent GP, Arbonés ML, de la Cruz X, Nieto M, Agell N, Mauvezin C, Martínez-Balbás MA
Progenitor proliferation during neurodevelopment requires tight coordination of epigenetic regulation and metabolism. However, the crosstalk between these processes remains poorly understood. To investigate this, we exam...Progenitor proliferation during neurodevelopment requires tight coordination of epigenetic regulation and metabolism. However, the crosstalk between these processes remains poorly understood. To investigate this, we examine in neural stem cells the role of PHF8, a histone demethylase whose mutations are linked to Siderius-Hamel syndrome, a rare neurodevelopmental disorder. Through an integrated multi-omics approach - combining transcriptomics, epigenomics, and metabolomics - we identify PHF8 as a key driver of the serine biosynthesis pathway, safeguarding the intracellular serine pool essential for neural progenitor proliferation. PHF8 fine-tunes chromatin accessibility at promoters of metabolic genes, ensuring their activation during development. Loss of PHF8 disrupts amino acid metabolism, blocks autophagy, and hinders vesicle formation. Ultimately PHF8 depletion leads to replication defects, DNA damage, and proliferation arrest. In vivo, PHF8 deficiency in mouse embryos halts neurogenesis, progenitor expansion, and neuron generation in the developing brain. These findings identify PHF8 as a key molecular link between chromatin regulation, metabolic control, and neural development, offering new insights into the epigenetic basis of neurodevelopmental and metabolic disorders.
During neurodevelopment neural stem cells give rise to a spatially patterned tissue in which a regionally differentially regulated balance between proliferation and differentiation produces the fine-tuned number of neuro...During neurodevelopment neural stem cells give rise to a spatially patterned tissue in which a regionally differentially regulated balance between proliferation and differentiation produces the fine-tuned number of neurons and macroglia necessary for a functional central nervous system. The cells driving these highly intricated developmental processes of patterning, growth and differentiation are constantly exposed to a mechanical environment that is, however, variable between different brain regions and along differentiation trajectories. Here we demonstrate that both, acute mechanical manipulations as well as a persistent change in the mechanical environment provided to human brain organoids, instruct neural stem cell lineage decisions. Furthermore, we dissect the underlying changes in the molecular program of organoid-resident cells by bulk- and single cell RNA-sequencing. These data reveal that mechanical manipulations impact on molecular programs governing early patterning events as well as cell-type-specific cellular metabolism. Thus, our results unravel a regulatory network linking mechanics and neural stem cell lineage decisions.
Our body is shaped during development under the control of genetic programs, but also under the influence of mechanical forces. Tissue growth and form is limited, biased and even instructed by mechanical forces. Brain de...Our body is shaped during development under the control of genetic programs, but also under the influence of mechanical forces. Tissue growth and form is limited, biased and even instructed by mechanical forces. Brain development is also under the influence of mechanical forces, but the extent of their effect, and the interplay with genetic programs, remain fundamentally unknown. New research in (Lampersperger et al, 2026) demonstrates that mechanical forces acting on human neural stem cells (NSCs) bias their cell fate, supporting a key role for mechanics in brain morphogenesis.
Telomeres cap the extremities of linear chromosomes and prevent their detection as DNA damage. Telomere uncapping poses a profound threat to genome integrity, yet the immediate consequences of transient uncapping remain...Telomeres cap the extremities of linear chromosomes and prevent their detection as DNA damage. Telomere uncapping poses a profound threat to genome integrity, yet the immediate consequences of transient uncapping remain unclear. In Saccharomyces cerevisiae, the Cdc13-Stn1-Ten1 complex limits resection, preventing DNA damage checkpoint activation. Here, using the temperature-sensitive cdc13-1 allele, we demonstrate that transient telomere uncapping rapidly induces extensive genomic rearrangements despite a functional DNA damage checkpoint. Two distinct rearrangement signatures are observed in surviving cells: recombination of the subtelomeric region mostly involving the Y' elements, and massively elongated telomeres up to 10 kb, a ~ 30-fold increase. Long-read sequencing evidences Y' element losses/amplifications, terminal duplications, and telomeric-circle-driven amplifications of telomere repeats. Rearrangements unfold over multiple generations and require the homologous recombination factor Rad52, the Polδ subunit Pol32, and partially Rad51 and Rad59. Remarkably, survivors with elongated telomeres demonstrate a robust Rad52-dependent resistance to subsequent telomere uncapping. Our findings provide novel insights into the consequences of transient telomere uncapping for genome stability, a process that might contribute to subtelomere and telomere dynamics and evolution.
Gim3 is an evolutionarily conserved component of the prefoldin chaperone complex, involved in protein folding. We previously found that GIM3 genetically interacts with many de novo mutations in Saccharomyces cerevisiae....Gim3 is an evolutionarily conserved component of the prefoldin chaperone complex, involved in protein folding. We previously found that GIM3 genetically interacts with many de novo mutations in Saccharomyces cerevisiae. Removing GIM3 from mutagenized S. cerevisiae cells significantly affected the fitness effect of mutations. This indicates that Gim3 might change the evolutionary impact of de novo mutations by either buffering (hiding) or potentiating (increasing) their phenotypic effects, depending on the environmental or genetic context. Here, we investigated Gim3's role in shaping the evolutionary fate of de novo mutations under fluconazole stress, an antifungal drug used to combat fungal infections. Applying both strong and moderate fluconazole stress in the presence or absence of GIM3 revealed that Gim3 potentiates fluconazole susceptibility (resistance and tolerance) by enabling mutations to have immediate phenotypic effects. Deleting GIM3 reduced growth in fluconazole in most mutants, indicating that GIM3 could be a promising target for new antifungal therapies against drug-resistant infections. Importantly, Gim3 also modulates fluconazole susceptibility of the fungal pathogen Nakaseomyces glabratus, further highlighting Gim3's role in fluconazole resistance and tolerance.