Molecular Cell

Filament-mediated repurposing of toxic dITP for immunity in the Kongming system Feng et al. uncover how a bacterial immune effector, KomBC, is activated by the toxic nucleotide dITP. A preassembled filament converts sparse, non-cyclic dITP signals into cooperative NADase activation, revealing a distinct ultrasensitive immune mechanism.

Online Now: Filament-mediated repurposing of toxic dITP for immunity in the Kongming system Online now:

Filament-driven activation of the Kongming antiviral system by deoxyinosine triphosphate Recently, the Kongming system has been identified as a bacterial anti-phage defense system relied on nucleobase-modified nucleotides for immune signaling. Zhen et al. determine a series of cryo-EM structures of this system, revealing that dITP binding induces filament assembly of KomBC, which elucidats the activation mechanism of the Kongming system.

Online Now: Filament-driven activation of the Kongming antiviral system by deoxyinosine triphosphate Online now:

Just out: new comprehensive review on signaling to make human ribosomes @cp-molcell.bsky.social. Can be found here authors.elsevier.com/sd/article/S.... Congrats to Baserga lab members Isabella Lawrence, Emily Sutton and Shivang Bhaskar @yalembb.bksy.social.

Lysosomes as hubs of metabolic sensing and cellular homeostasis Jain et al. review how lysosomes act as signaling hubs that couple nutrient export to sensing pathways controlling growth, stress responses, and organelle crosstalk. They highlight immune- and neuron-specific lysosomal programs that integrate metabolic status and organelle health to shape tissue physiology.

Online Now: Lysosomes as hubs of metabolic sensing and cellular homeostasis Online now:

Mitochondria as sources and targets of cellular signaling Meichsner et al. review recent insights into mitochondria as dynamic signaling hubs. The authors describe how structural plasticity and interorganellar communication enable mitochondria to serve as both sources and targets of signaling, coordinating stress responses, metabolic adaptation, and innate immune pathways to safeguard cellular homeostasis.

Online Now: Mitochondria as sources and targets of cellular signaling Online now:

Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus Lawrence et al. examine how ribosome production in the eukaryotic nucleolus is coordinated by cytoplasmic processes to maintain appropriate ribosome numbers. The authors highlight regulatory inputs from cytoplasmic signaling, mitosis, and cytoplasmic organelles that converge on nucleolar function, and they discuss how disruption of these pathways contributes to human disease.

Online Now: Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus Online now:

Coordinating mRNA maturation: The U1 relay model Yoon et al. provide a broad overview of how all the RNA processing steps are intimately linked to transcription and to one another. They propose a U1 relay model as a general framework for understanding the mechanism for coupling transcription and RNA processing.

Online Now: Coordinating mRNA maturation: The U1 relay model Online now:

Mito-nuclear communication: From cellular responses to organismal health Mito-nuclear communication extends beyond the cell. This review explores how mitochondrial stress engages UPRmt and ISRmt signaling and scales through mitokines and neural circuits to shape systemic physiology, resilience, and aging.

Online Now: Mito-nuclear communication: From cellular responses to organismal health Online now:

Why m⁶A? An RNA surveillance model Dierks and Schwartz discuss the m6A surveillance model, proposing that m6A flags “undesirable” intron-less RNAs (e.g., transposons) for decay. This provides a mechanism to distinguish “legitimate” spliced mRNAs and potentially suppress harmful RNA.

Online Now: Why m⁶A? An RNA surveillance model Online now:

Ribosome-NAC collaboration: A regulatory platform for cotranslational chaperones, enzymes, and targeting factors How do ribosomes direct nascent chains toward folding or organelle targeting? This review outlines emerging mechanisms by which the nascent polypeptide-associated complex (NAC) decodes early signals at the ribosomal tunnel and orchestrates the selective engagement of cotranslational factors to maintain fidelity in protein biogenesis.

Online Now: Ribosome-NAC collaboration: A regulatory platform for cotranslational chaperones, enzymes, and targeting factors Online now:

A Heavy Chain Reaction: Unraveling loop extrusion dynamics during VDJ recombination 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.

A Heavy Chain Reaction: Unraveling loop extrusion dynamics during VDJ recombination

Fin(e)-tuning ferroptosis 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.

Fin(e)-tuning ferroptosis

Whaling for the mechanisms of cancer resistance and long lifespans 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.

Whaling for the mechanisms of cancer resistance and long lifespans

Anchoring the acentric: How retention elements give ecDNA immortality 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.

Anchoring the acentric: How retention elements give ecDNA immortality

EGO complex at 20: The Rag GTPase-TORC1 nutrient-sensing blueprint Two decades of discoveries following the identification of the EGO complex point to a conserved framework for nutrient-dependent (m)TORC1 signaling, where regulation of both the kinase’s localization and signaling amplitude shapes the pathway’s output.

EGO complex at 20: The Rag GTPase-TORC1 nutrient-sensing blueprint

Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network Halim et al. show that chronic activation of the proteostasis regulator HSF1 broadens the mutational space accessible to the tumor suppressor p53. HSF1 enhances the fitness of destabilizing, dominant-negative p53 variants, suggesting that elevated proteostasis capacity can directly promote the emergence and persistence of oncogenic mutations in cancer cells.

Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network

Delineating the copy-number substructure of metastatic tumors with CopyKit Wang et al. present CopyKit, a scalable and comprehensive toolkit for analyzing single-cell DNA copy-number data and estimating integer copy-number states with scquantum. Applied across primary and metastatic tumors, CopyKit resolves subclonal structure, reconstructs metastatic lineages, and reveals spatial heterogeneity in tumors.

Delineating the copy-number substructure of metastatic tumors with CopyKit

A mouse circadian proteome atlas Otobe et al. build a searchable web tool to explore spatiotemporal profiles of about 19,000 proteins across 32 tissues and brain regions, revealing circadian protein and phosphorylation rhythms in whole-cell and nuclear proteomes.

A mouse circadian proteome atlas

IFI16 senses and protects stalled replication forks Gamble et al. demonstrate that detection of stalled replication forks by the innate immune sensor IFI16 induces an early STING-dependent pro-inflammatory cytokine response independently of cGAS and DNA damage. Furthermore, IFI16 exhibits dual functionality during replication stress by protecting stalled, remodeled replication forks from nucleolytic degradation.

IFI16 senses and protects stalled replication forks

Capsid restructuring activates semi-conservative dsRNA transcription in cystovirus ɸ6 Ilca et al. uncover how the double-stranded RNA cystovirus ɸ6 activates its semi-conservative transcription inside its double-layered capsid. Using cryogenic electron microscopy and localized reconstruction, they visualize how nucleotide binding triggers shedding of the outer capsid layer, expansion of the inner layer, and assembly of a triskelion-shaped complex of the minor protein P7 at opposite poles of the spooled genome. These complexes organize the viral RNA-dependent RNA polymerases (P2) to initiate transcription, with the newly synthesized mRNA exiting through the hexameric P4 channels. The results reveal a multi-step structural transition that converts a quiescent capsid into an active transcriptional nanomachine.

Capsid restructuring activates semi-conservative dsRNA transcription in cystovirus ɸ6

Chromatin folding principles underlying the generation of antibody diversity Ollikainen et al. combined biophysical simulations and experimental data to model chromatin structure and dynamics of the 3 Mb mouse Igh locus. The study reveals mechanisms of long-range genome communication and chromatin folding principles that enable antigen receptor diversity.

Chromatin folding principles underlying the generation of antibody diversity

ICAM1 mRNA entraps ILF2/ILF3 to inhibit transcription of EIF4E and global protein synthesis Jiang et al. show that ICAM1 mRNA suppresses cell proliferation, in contrast to the protein’s pro-proliferative role in the same cell. This finding highlights mRNA functions independent of their proteins and challenges the interpretation of protein phenotypes solely on mRNA silencing or the central dogma.

ICAM1 mRNA entraps ILF2/ILF3 to inhibit transcription of EIF4E and global protein synthesis

CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity Liu et al. show that CASTOR1 and CASTOR2 bind arginine in a similar manner and form comparable homodimers. However, CASTOR1 senses low arginine levels, while CASTOR2 responds to high levels. Together, they function as dual arginine sensors, modulating mTORC1 activity by regulating GATOR2-GATOR1 interaction.

CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity

PDCD5 promotes substrate release from the TRiC complex in cilia and flagella Wei et al. present structural analyses of the PDCD5-TRiC complex in open states, revealing the involvement of PDCD5 in substrate release from the TRiC chamber.

PDCD5 promotes substrate release from the TRiC complex in cilia and flagella

BRD2 bridges TFIID and MOF-H4K16ac-containing nucleosomes to promote transcriptional initiation Zheng et al. reveal a bromodomain-dependent role for BRD2 in transcriptional initiation and demonstrate that BRD2’s bromodomains anchor it to chromatin via MOF-acetylated histone H4K16. BRD2’s C-terminal domain facilitates interaction with RNA Pol II basal initiation factor TFIID. They also show that different BET domains have different acetyl-histone preferences.

BRD2 bridges TFIID and MOF-H4K16ac-containing nucleosomes to promote transcriptional initiation

Read our latest issue here www.cell.com/molecular-ce...

The ribosome synchronizes folding and assembly to promote oligomeric protein biogenesis Large oligomeric proteins constitute a major fraction of proteomes, but are difficult to refold in vitro, raising the question of how cells direct their biogenesis. Roeselová and Shivakumaraswamy et a...

Our latest cotranslational folding story is now published @cp-molcell.bsky.social. Really cool (I think) new ideas about how exactly the ribosome directs folding and assembly to make sure complicated proteins mature efficiently in cells.
www.cell.com/molecular-ce...

RNA anti-CRISPRs deplete Cas proteins to inhibit the CRISPR-Cas system Gao et al. uncover the structural basis by which RNA anti-CRISPRs (Racrs) inhibit the type I-F CRISPR-Cas system and demonstrate that Racrs competitively divert Cas6f and Cas7f into aberrant assemblies. This sequestration blocks formation of the functional Csy surveillance complex, thereby disabling antiviral defense.

RNA anti-CRISPRs deplete Cas proteins to inhibit the CRISPR-Cas system

The ribosome synchronizes folding and assembly to promote oligomeric protein biogenesis Large oligomeric proteins constitute a major fraction of proteomes, but are difficult to refold in vitro, raising the question of how cells direct their biogenesis. Roeselová and Shivakumaraswamy et al. show how the ribosome orchestrates efficient cotranslational folding and assembly.

Online Now: The ribosome synchronizes folding and assembly to promote oligomeric protein biogenesis Online now:

Molecular mechanism of MDA5 nucleation and filament formation by LGP2 Kurihara et al. reveal that LGP2 binds dsRNA ends and translocates internally to nucleate MDA5 filaments. This mechanism allows MDA5 to recognize immunologically elusive short viral RNAs. The resulting heterofilament microclusters robustly trigger MAVS signaling, broadening the scope of innate immune detection.

Online Now: Molecular mechanism of MDA5 nucleation and filament formation by LGP2 Online now: