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In living systems, ATP provides an energetic driving force for protein synthesis and modification. Now, an engineered enzymatic tool has been developed for high-yield, ATP-driven protein bioconjugation through versatile thioester intermediates. This method mimics biological strategies for peptide bond formation to enable precision chemical modification of proteins in vitro.

Here the authors show that MRAP2 tunes the melanocortin-4 receptor by boosting its G-protein signaling while limiting β-arrestin2 interaction and destabilizing receptor oligomers, shaping appetite regulation.

Issa et al. show that the ciliary small guanosine triphosphatase Arl3 displaces the inhibitory regulator Shulin/DNAAF9 from the outer dynein arm, leading to motor activation.

Here, Santamaria de Souza et al. explore the context-dependent fitness effects of glpT-deficiency in Salmonella enterica, showing mutants thrive in the gut lumen but are counter-selected by macrophages, highlighting antagonistic pleiotropy and niche-dependent adaptation.

Cell state plasticity of neuroblastoma cells is linked to therapy resistance. Here, the authors develop a transcriptomic and epigenetic map of indisulam (RBM39 degrader) resistant neuroblastoma, demonstrating bidirectional cell state switching accompanied by increased NK cell activity, which they therapeutically enhance by the addition of an anti-GD2 antibody.

The authors develop and characterise a selective Greatwall inhibitor, C-604, and show that its cytotoxicity stems from PP2A-B55α hyperactivation. They identify B55α and Greatwall levels as biomarkers of responses to Greatwall-targeted therapy.

SCRaMbLE can optimise traits via gene rearrangement but is limited by screening. Here the authors use FACS and long-read sequencing with iterative SCRaMbLE to map genotype diversity and gene arrangements, identifying solutions for improving genome design.

Synthetic receptors are a powerful approach for engineering cell-based therapies that can sense and respond to their environment. Here cytokine receptor domains have been repurposed to develop engineered T cells that can sense and respond to cues associated with cancer or immune dysfunction.

In situ cryoEM and modelling of the Campylobacter jejuni flagellar motor characterize the periplasmic scaffold and the structural basis for increased torque generation.

Precise and scalable regulation of gene expression in mammalian cells is challenging. Here, the authors created a highly tunable CRISPR-based synthetic transcription system for programmable control of mammalian gene expression and cellular activity.

A metabolic system of engineered biocatalysts using the noncanonical cofactor nicotinamide mononucleotide is established for biomanufacturing in cell-free systems and in Escherichia coli without interference from nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate.

Synthetic RNA-based devices can dynamically control a wide range of processes. Here the authors develop a quantitative and high-throughput mammalian cell-based RNA-seq assay to efficiently engineer ribozyme switches.

Prime-editing mouse models enable the study of specific cancer mutations in vivo.

Peptidoglycan biosynthesis is regulated by a feedback mechanism preventing the pathway from sequestering essential lipid carriers used to assemble and transport surface glycan subunits.

DNA damage threatens genomic stability and must be efficiently repaired. Here, the authors identify a role for the RNA methyltransferase NSUN2 in facilitating DICER-dependent processing of damage-responsive transcripts, promoting efficient double-strand break repair.

Human pathways acting on nuclear ncRNAs have been refractory to forward genetics. Here, the authors develop a forward genetic approach that identifies such pathways and show DDX59 is required for minor intron splicing, suggesting a mechanism for its association with Oral-Facial-Digital syndrome.

Context-dependent, responsive synthetic promoters are crucial for a wide range of applications, yet currently available options are limited. Here, authors develop a library of thousands of candidate promoters based on binding motifs of hundreds transcription factors for use in mammalian cells.

The parasite Cryptosporidium has a reduced genome and is dependent on glycolysis for energy production. Here, Xu et al demonstrate that multiple pathways and glucose transporters exist in this organism which are essential for growth and facilitate energy acquisition and utilization.

A study uses single-molecule footprinting to measure protein occupancy at regulatory elements on individual molecules in human cells and describes how different properties of transcription factor binding contribute to gene expression.

The expansion of clones with distinct SERPINA1 somatic mutants in the livers of alpha-1 antitrypsin deficiency (A1AT) patients is consistent with convergent evolution. These variants interfere with the auto-polymerization and intra-ER accumulation of the Z-A1AT protein, thus highlighting potentially targetable domains.

MGAT1 is a glycosyltransferase critical for the synthesis and maturation of complex N-glycans. Here, the authors show that MGAT1 modulation of CD73 glycosylation and function regulates tumor immune response in triple-negative breast cancer.

Managing power exhaust in fusion reactors is a key challenge, especially in compact designs for cost-effective commercial energy. This study shows how alternative divertor configurations improve exhaust control, enhance stability, absorb transients and enable independent plasma regulation.

With redox-linked synthetic biology and electrobiofabrication, electronic information can be transmitted in a bidirectional manner between biology and electronics. Here the authors design an electrogenetic platform that allows real time electronic control of biological functions from proteins and gene circuits to cell consortia.

Transplantation of allogeneic hematopoietic stem cells (HSCs) is the only reported cure of HIV-1. Here, authors describe an autologous HSC transplant therapy with cells engineered for multilayered resistance to HIV-1 through CCR5 knockout and secretion of HIV inhibiting antibodies by B cell progeny.

Development of a generalized method for dual site-specific incorporation of nonnatural photocaged and photoreactive amino acids into proteins expressed in live cells enabled engineering of a photoreactive photoactive antibody fragment.

Sequencing analysis of tamoxifen-associated uterine cancers and further in vivo analyses suggest that the drug tamoxifen can activate the PI3K pathway in the absence of oncogenic mutations.

Telomere length is tightly controlled in normal cellular function and the human population. Here, the authors reveal that telomere synthesis is bidirectionally constrained by cellular nucleotide pools, in a manner which may be therapeutically manipulated.

Synthetic biology offers the ability to explore new ways of manipulating gene expression and function. Here the authors demonstrate an electrogenetic device that allows control of transcription by an exogenous electrical signal.

Characterization of bacterial auxin degradation loci and their regulators reveals two distinct types across plant microbiome species, where only one, exemplified in Variovorax species, can interfere with root growth inhibition in a complex synthetic microbial community.

Africa-specific genetic variation on chromosome 1 near CHD1L is associated with HIV replication in vivo.

Clinically approved drugs can be used to control chemically induced dimerization and program mammalian cellular behaviors.

Real-time biosensors have been developed for visualizing kinase activity dynamics, but they are confronted with many challenges. Here, the authors develop a light-gated KINACT integrator for post hoc analysis of transient kinase activity and signalling manipulation.

Cyclic and mirror-image variants of de novo-designed proteins effectively bind and clear small-molecule drugs in vivo in less than 30 min, highlighting the applicability of computational tools to produce protein antidotes.

Nanoparticles are a promising approach to increase immunogenicity of protein antigens for vaccines. Here, Brouwer et al. design self-assembling, two-component protein NPs that present native-like SOSIP trimers of HIV envelope protein and determine immunogenicity in a small animal model.

JMML is an aggressive hematologic malignancy with myeloproliferative characteristics affecting young children. Here the authors report that C-type lectin-like molecule-1 (CLL-1) is upregulated in JMML and they develop CLL-1 CAR T cells showing in vitro and in vivo anti-JMML activity.

Acyltransferase activity of the enzyme bile salt hydrolase is identified and shown to mediate microbial bile acid conjugation, diversifying the bile acid pool and expanding their role in gut physiology.

Using cryo-electron microscopy, the authors describe the structure and function of a molecular motor powering both the Bacteroidetes type 9 protein secretion system and the associated gliding motility apparatus.