Muralidharan A, Costa AR, Fierlier D
… +8 more, van den Berg DF, van den Bossche H, Zoumaro-Djayoon AD, Rodríguez-Molina A, Pabst M, Pacesa M, Correia BE, Brouns SJJ
Jumbo phages protect their genomes from DNA-sensing bacterial defense systems by enclosing them within vesicles and nucleus-like compartments. Very little is known about defense systems specialized to counter these phage...Jumbo phages protect their genomes from DNA-sensing bacterial defense systems by enclosing them within vesicles and nucleus-like compartments. Very little is known about defense systems specialized to counter these phages. Here, we show that AVAST type 5 (Avs5) systems, part of the signal transduction ATPases of numerous domains (STAND) superfamily, confer conserved immunity against jumbo phages. Using fluorescence microscopy and biotin proximity labeling, we demonstrate that Avs5 localizes to early infection vesicles, where it senses an essential, early-expressed phage protein named JADA (Jumbo phage Avs5 Defense Activator). Recognition of phage infection triggers the Sir2-like effector domain of Avs5 across three Avs5 clades, resulting in rapid NAD hydrolysis, disruption of phage nucleus formation, and arrest of infection. These findings reveal a spatially coordinated bacterial immune strategy that targets an early vulnerability in jumbo phage infection.
Collaborations are critical features of modern academic science. As biological problems get more complex, larger teams become necessary. However, there is an increased level of friction in coordinating activities and att...Collaborations are critical features of modern academic science. As biological problems get more complex, larger teams become necessary. However, there is an increased level of friction in coordinating activities and attributing credit in large-scale scientific collaborations. Simple organizational principles and rules of conduct can be powerful lubricants of successful interactions.
Computational approaches are necessary to leverage the potential of large datasets and generate new hypotheses. At the same time, testing these predictions in biological systems remains key to truly understanding the und...Computational approaches are necessary to leverage the potential of large datasets and generate new hypotheses. At the same time, testing these predictions in biological systems remains key to truly understanding the underlying mechanisms. Once largely siloed, collaboration between bench and computational work is becoming indispensable for many areas of research. For our collaboration focus issue, we spoke with scientists who are integrating different approaches to gain new insights about their experiences in bridging the two.
Coordination and collaboration between biological systems is shaped over time by environmental pressures. Collaborations between scientists also evolve and grow in directions that would have been hard to predict from the...Coordination and collaboration between biological systems is shaped over time by environmental pressures. Collaborations between scientists also evolve and grow in directions that would have been hard to predict from their outset. Sara Miller spoke with Felicia Basilicata and Claudia Keller Valsecchi about their long-term collaboration. The two started working together as postdocs and started their independent groups in Mainz, Germany and are now navigating continued collaboration after relocating to institutions in different cities. How do you start a collaboration and maintain it, even when you don't always agree? An edited version of this conversation is presented below.
This issue, centered around the theme of collaboration, features reviews exploring how different parts of the cell or different macromolecular complexes work together to ensure the proper functioning of the cell. We also...This issue, centered around the theme of collaboration, features reviews exploring how different parts of the cell or different macromolecular complexes work together to ensure the proper functioning of the cell. We also ask researchers to share their personal approaches to collaboration in scientific research.
Transcription condensates are liquid-like compartments where transcription factors, co-activators, and RNA polymerases are selectively enriched and regulate transcription initiation of associated genes. While the princip...Transcription condensates are liquid-like compartments where transcription factors, co-activators, and RNA polymerases are selectively enriched and regulate transcription initiation of associated genes. While the principles governing the enrichment of proteins within transcription condensates are being elucidated, mechanisms that coordinate condensate dynamics with other nuclear processes, such as DNA replication, have not been identified. We show in human cells that at the G1/S cell-cycle transition, large transcription condensates form at histone locus bodies (HLBs) in a cyclin-dependent kinase 1 and 2 (CDK1/2)-dependent manner. By mid-S phase, ataxia-telangiectasia and Rad3-related kinase (ATR) accumulates within HLBs and dissolves the associated condensates via its downstream effector, CHK1. Failure to dissolve condensates results in overexpression of linker H1 histones and nucleus-wide DNA damage. Moreover, an imbalance in the different linker histones accentuates DNA damage in ATR-CHK1-deficient cells. Our work reveals how transcription condensates are precisely controlled in the S phase to fine-tune gene activation and safeguard genome stability.
Abortive infection systems protect bacteria by triggering self-destruction in response to phage attack. Most known systems rely on stable cyclic nucleotides that accumulate to stoichiometric levels to activate effectors;...Abortive infection systems protect bacteria by triggering self-destruction in response to phage attack. Most known systems rely on stable cyclic nucleotides that accumulate to stoichiometric levels to activate effectors; the Kongming (Kom) system employs the toxic metabolite deoxyinosine triphosphate (dITP) as its signaling molecule. Here, we show that the Escherichia coli KomB-KomC (KomBC) complex forms a preassembled filament that remains inactive until dITP binding induces cooperative allosteric activation. KomB, a homolog of the nucleotide-hydrolyzing enzyme HAM1, has lost catalytic activity but evolved a high-affinity, hydrolysis-resistant binding pocket for dITP. Interestingly, substoichiometric dITP binding is sufficient to activate adjacent KomC NADase domains, which propagate activation cooperatively along the filament. This filament-based architecture enables ultrasensitive, long-range allosteric signaling in response to a low-abundance and short-lived metabolite. Our findings reveal an ultrasensitive immune strategy that transforms a toxic byproduct into a robust antiviral trigger, expanding the known repertoire of bacterial defense strategies.
Nucleotide-derived second messengers are frequently deployed by bacteria to activate effector proteins to mediate the immunity. The Kongming system uses deoxyinosine triphosphate (dITP) to trigger nicotinamide adenine di...Nucleotide-derived second messengers are frequently deployed by bacteria to activate effector proteins to mediate the immunity. The Kongming system uses deoxyinosine triphosphate (dITP) to trigger nicotinamide adenine dinucleotide (NAD) depletion via the Sir2-domain protein KomC. We reveal that dITP binding to the KomB-KomC (KomBC) complex stabilizes KomB dimerization, initiating hierarchical allosteric changes. This drives KomBC filament assembly, which is essential for activating the NADase activity of KomC. Cryo-EM structures of apo-, dITP-bound, NAD-bound and postcatalytic KomBC filaments show the structural landscape of how dITP-induced remodeling reshapes the catalytic pocket of KomC, enabling NAD hydrolysis. Mutagenesis confirms that filament assembly and allostery are critical for catalysis. These findings elucidate the structural basis for the recognition of the nucleotide derivative signaling molecule, the assembly and the filament-mediated allosteric activation mechanism in prokaryotic immunity and a distinct variation of Sir2 NADase activation.
Ribosome biogenesis is a complex, multi-step cellular process that begins in the nucleolus and produces ribosomes that translate mRNA into proteins in the cytoplasm. This process is essential for cellular growth yet is r...Ribosome biogenesis is a complex, multi-step cellular process that begins in the nucleolus and produces ribosomes that translate mRNA into proteins in the cytoplasm. This process is essential for cellular growth yet is resource intensive. It is therefore tightly coordinated with cytoplasmic requirements, energy availability, and the cell cycle through several kinase signaling pathways. Increasing evidence indicates that proteins shared between the cytoplasm and nucleolus may enhance this coordination. Here, we evaluate the interplay between the cytoplasm and nucleolus in human cells, presenting an intricate bidirectional regulatory network with emerging clinical relevance. We describe the phosphorylation events that promote ribosome biogenesis during interphase, focusing on mammalian target of rapamycin complex 1 (mTORC1), extracellular signal-regulated kinase (ERK), and casein kinase II (CK2). By contrast, protein phosphorylation inactivates ribosome biogenesis during mitosis. We further summarize several factors shared among the mitotic machinery, cytoplasmic organelles, and the nucleolus. Moreover, we highlight the mounting evidence that dysregulated cytoplasmic-nucleolar feedback contributes to the progression of several diseases.
The co-evolution of mitochondria and the nucleus established constant mito-nuclear communication that is essential for both cellular and organismal homeostasis. At the cell-autonomous level, mitochondrial perturbations a...The co-evolution of mitochondria and the nucleus established constant mito-nuclear communication that is essential for both cellular and organismal homeostasis. At the cell-autonomous level, mitochondrial perturbations activate retrograde pathways such as the mitochondrial unfolded protein response (UPR) and the mitochondrial integrated stress response (ISR), which couple organelle dysfunction to nuclear transcriptional programs, thereby promoting mitochondrial function and preserving cellular integrity. Importantly, this communication is not confined to individual cells but extends across tissues to coordinate systemic adaptations. Stress signals can be sensed, broadcasted through secreted mitokines and neural circuits, and then interpreted by distal organs to coordinate systemic adaptations. These systemic responses integrate metabolism, immunity, and behavior, conferring resilience to stress and shaping the trajectory of aging. Understanding this multi-layered communication, from the organelle to the organism and its microbial ecosystem, promises new therapeutic strategies to enhance mitochondrial function, promote resilience, and extend healthspan.
Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular...Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.
Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises fr...Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises from a unique combination of structural and functional plasticity, allowing them to sense, integrate, and respond to a wide variety of cellular cues. Mitochondria are highly dynamic-they can fuse and divide, pinch off vesicles, and move around, facilitating interorganellar communication. Moreover, their ultrastructural peculiarities enable tight regulation of fluxes across the inner and outer mitochondrial membranes. As organelles of proteobacterial origin, mitochondria harbor danger signals and require protection from the consequences of membrane damage by efficient quality control mechanisms. However, mitochondria have also been co-opted by eukaryotic cells to react to cellular damage and promote effective immune responses. In this review, we provide an overview of our current knowledge of mitochondria as both sources and targets of cellular signaling.
mRNA maturation requires precise coordination among transcription, 5' capping, splicing, and 3' end formation. Recent biochemical, structural, and genomic studies demonstrate that these processes are tightly coupled thro...mRNA maturation requires precise coordination among transcription, 5' capping, splicing, and 3' end formation. Recent biochemical, structural, and genomic studies demonstrate that these processes are tightly coupled through dynamic interactions among RNA polymerase II, the spliceosome, and cleavage-polyadenylation complexes. Here, we synthesize current mechanistic insights into how transcription elongation factors and RNA processing machineries communicate to ensure efficient and accurate transcript maturation. We propose a "U1 relay" model as a unified framework for understanding co-transcriptional splicing and 3' end formation. We further discuss how RNAs are sorted into nuclear retention/degradation or export pathways based on the RNA processing status. Importantly, RNA processing factors not only act downstream of transcription but also feed back to modulate transcriptional elongation, pausing, and termination, thereby reinforcing bidirectional coupling between RNA synthesis and processing.
N6-methyladenosine (m⁶A) is the most abundant internal modification of mRNA and is most strongly linked to promoting mRNA decay. Why transcripts are born with a death-promoting mark has remained unclear. A previously pro...N6-methyladenosine (m⁶A) is the most abundant internal modification of mRNA and is most strongly linked to promoting mRNA decay. Why transcripts are born with a death-promoting mark has remained unclear. A previously proposed "fast-track" model posited regulated, gene-specific modulation of m⁶A to coordinate translation and turnover. However, emerging evidence reveals that m⁶A is broadly and mostly constitutively installed at all DRACH motifs except in the vicinity of splice sites, all of which challenge a fast-track model. We propose an "m⁶A surveillance model": properly spliced transcripts mostly evade methylation, while unspliced, transposon-derived, viral, or aberrant RNAs are hypermethylated and selectively degraded. This model reframes m⁶A as a default quality-control mark that flags undesirable unspliced RNAs for removal. We discuss literature supporting and challenging this model as well as experimental priorities that could allow for a more thorough investigation of this model.
Protein biogenesis requires the ribosome to collaborate with a diverse set of cotranslational factors that shape the fate of nascent chains. These interactions must be precisely choreographed: while cytonuclear proteins...Protein biogenesis requires the ribosome to collaborate with a diverse set of cotranslational factors that shape the fate of nascent chains. These interactions must be precisely choreographed: while cytonuclear proteins require immediate N-terminal maturation and folding, endoplasmic reticulum (ER) and mitochondrial proteins must be maintained in an unfolded state for targeting to their organelles. Reconciling these opposing demands requires a highly selective sorting mechanism operating at the ribosomal exit tunnel. Recent studies identify the conserved nascent polypeptide-associated complex (NAC) as a central coordinator of this process. By sensing nascent signals and dynamically modulating factor access to the ribosome, NAC directs substrates toward the appropriate maturation or targeting pathway. This emerging framework positions NAC as a molecular hub that organizes cotranslational interactions into efficient and orderly protein-biogenesis pathways. In this review, we discuss the mechanistic principles underlying NAC function and consider broader implications for how ribosome-associated networks enforce fidelity in protein biogenesis.
2025 marked the 20th anniversary of a discovery that reshaped the understanding of nutrient signaling. How nutrients, specifically amino acids, impinge on the target of rapamycin complex 1 (TORC1), a eukaryotic protein k...2025 marked the 20th anniversary of a discovery that reshaped the understanding of nutrient signaling. How nutrients, specifically amino acids, impinge on the target of rapamycin complex 1 (TORC1), a eukaryotic protein kinase complex and growth regulator, long remained a mystery. Identification of the EGO complex in Saccharomyces cerevisiae provided the functional link between Rag GTPases and TORC1 reactivation in a nutrient-responsive context, revealing a vacuolar membrane-based growth control mechanism and pinpointing glutamine as a key metabolite. Subsequent work across yeast, flies, and mammals uncovered a conserved regulatory logic in which Rag GTPases integrate amino acid signals with spatial control of TORC1. We now appreciate that scaffolds, GAP complexes, and nutrient sensors set Rag GTPase nucleotide states to position TORC1 at membranes, while allosteric activators amplify the kinase's catalytic output. These insights highlight how early work in yeast set the stage for discoveries leading to a cross-species framework for nutrient-TORC1 coupling with broad implications for physiology, disease, and therapeutic targeting.
In a recent Nature article, Venkat Sankar et al. uncover ecDNA harboring specific DNA sequences called retention elements, contact regions of mitotic chromosomes that are bookmarked by transcription factors and chromatin...In a recent Nature article, Venkat Sankar et al. uncover ecDNA harboring specific DNA sequences called retention elements, contact regions of mitotic chromosomes that are bookmarked by transcription factors and chromatin proteins to promote coordinated inheritance. Retention elements are essential for ecDNA amplification, even in the absence of positive selection, and their silencing can lead to rapid ecDNA depletion.
Bowhead whales have the longest lifespan of all vertebrates, living over 200 years. The mechanisms responsible for their lifespan are mostly unknown. In a recent study in Nature, Firsanov et al. reveal that bowhead whale...Bowhead whales have the longest lifespan of all vertebrates, living over 200 years. The mechanisms responsible for their lifespan are mostly unknown. In a recent study in Nature, Firsanov et al. reveal that bowhead whales have evolved more efficient DNA-repair mechanisms.
In a recent issue of Cell, Lorenz et al. report that the anti-ferroptosis protein GPX4 anchors to membranes using a unique "fin-loop" element that is disrupted in an ultrarare human disease, decoupling enzyme activity fr...In a recent issue of Cell, Lorenz et al. report that the anti-ferroptosis protein GPX4 anchors to membranes using a unique "fin-loop" element that is disrupted in an ultrarare human disease, decoupling enzyme activity from biological function and causing neurodegeneration.
In this issue of Molecular Cell, Ollikainen et al. combine computational simulations with empirical data to reveal how the dynamics of chromatin loop extrusion at the immunoglobulin heavy chain locus enable comparable fr...In this issue of Molecular Cell, Ollikainen et al. combine computational simulations with empirical data to reveal how the dynamics of chromatin loop extrusion at the immunoglobulin heavy chain locus enable comparable frequencies of VDJ recombination across megabases of chromatin.