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A Gifsy-1 prophage–encoded higher eukaryotes and prokaryotes nucleotide-binding protein, HepS, senses Siphoviridae infection, activates abortive defence by cleaving host transfer RNAs, blocks rival phages and avoids self-targeting via tail-tip variation.

Multidrug efflux pumps help bacteria survive stress and promote antibiotic resistance. Here, authors define the molecular detail of an anaerobic-connected pump MdtF uncovering acid-responsive activity which may enable toxin control in certain niches.

How the complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth is explored.

Cas12a3 nucleases constitute a distinct clade of type V CRISPR–Cas bacterial immune systems that preferentially cleave the 3′ tails of tRNAs after recognition of target RNA to induce growth arrest and block phage dissemination.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

Cells of the adaptive immune system hold a grudge: on re-encountering a pathogen, they show a robust protective response. It seems that natural killer cells of the innate immune system might also have this ability.

The authors reveal that the C-terminal tail anchors of BCL-2 family proteins control BH3 binding and cell survival by allosteric regulation at the mitochondrial membrane, involving BAX recruitment and complex disruption upon BH3 mimetic antagonism.

The DNA-dependent protease SPRTN cleaves toxic DNA-protein crosslinks (DPCs). Here, the authors show that SPRTN is activated by DPC-ubiquitylation through an allosteric ubiquitin binding interface. This regulatory mechanism enables precise control of SPRTN activity during DNA repair.

Ubiquitination is a versatile modification system in eukaryotic cells. Here, the authors unveil that the ubiquitin ligase HUWE1 can modify drug-like small-molecule substrates, beyond proteins. This discovery may be harnessed to develop specific tool substrates or inhibitors of HECT-type ligases.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

Here, authors report the structure of the augmin’s CH domain bound to the microtubule lattice and show that its Haus8 subunit binds tubulin tails. Both domains are critical for microtubule binding and for microtubules to branch at shallow angles.

This study reveals that caveolae and caveolin-1 form a front-rear asymmetry in migrating cells, coupling membrane tension to RhoA-GEF recruitment and activation. This mechanosensing feedback regulates cell polarity and promotes persistent migration.

An approach combining BONCAT, stable isotope probing and metaproteomics showcases the hidden metabolic interconnectivity of microorganisms within an anaerobic digestion community.

The microbial metabolite trimethylamine (TMA), the precursor of TMAO, which is associated with adverse cardiometabolic outcomes, is shown to have beneficial metabolic and anti-inflammatory effects in the host in the context of obesity.

The BRCA2 tumour suppressor protein is known to play an important role in homologous recombination. Here the authors reveal how the phosphorylation of BRCA2 by Polo-like kinase 1 (PLK1) contributes to the regulation of mitosis.

Proteins are inserted into the outer mitochondrial membrane by the mitochondrial sorting and assembly machinery, two structural forms of which are presented here, suggesting the mechanism involved.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Scaffolding protein ankyrin-B, implicated in cardiometabolic syndrome, enables mitochondrial fission and flexibility of nutrient utilization under energetic stress in skeletal muscle to support energy production and optimal exercise capacity.

Maintenance and quality control of the mitochondrial respiratory chain complexes responsible for bulk energy production are unclear. Here, the authors show that the mitochondrial protease ClpXP is required for the rapid turnover of the core N-module of respiratory complex I, which happens independently of other modules in the complex.

Williams et al. report a growth arrest mechanism in residual cancer persister cells through targeted therapy-induced upregulation of type I interferon signalling, which is negatively regulated by apoptotic DNA endonuclease DFFB to allow tumour relapse.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Wild chimps in Bossou, Guinea, use stone tools to crack nuts. They show individual variation in how efficient they are, and some individuals are consistently more efficient than others.

Here the authors characterize a single-domain antibody that broadly neutralizes SARS-CoV-2 variants with high potency by targeting the heptad repeat 2 (HR2) coiled coil, conserved in sarbecoviruses. Binding to its quaternary epitope blocks membrane fusion, by locking HR2 in its prefusion conformation.

Bacillus thuringiensis israelensis (Bti) produces the naturally-crystalline proteinaceous toxin Cyt1Aa that is toxic to mosquito larvae. Here the authors grow recombinant nanocrystals of the Cyt1Aa protoxin in vivo and use serial femtosecond crystallography to determine its structure at different redox and pH conditions and by combining their structural data with further biochemical, toxicological and biophysical analyses provide mechanistic insights into the Cyt1Aa bioactivation cascade.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

It is shown that mice lacking the renal Rhcg factor have impaired ammonium excretion, thereby refuting the long-standing notion that rapid transepithelial transport of non-ionic ammonia occurs solely by lipid phase diffusion. In addition, it is shown that Rhcg is required for epididymal fluid homeostasis with clear consequences for male fertility.

Investigating how proteins acquire specific metals in cells is challenging. Here, the authors use a cyanobacterial Mn^II-cupin (MncA) as a metal trap to test predictions of metalation, and determine metal-preferences by refolding MncA in buffered competing metals.

Cyclin-dependent kinase 7 (Cdk7) is required in cell-cycle and transcriptional regulation. It is regulated by two phosphorylations in the activation segment. Here, the authors report a structure of the human Cdk7/Cyclin H/Mat1 complex containing both phosphorylations, with further insights into the regulatory mechanisms.

Proteins with small structural modifications at specific sites are valuable, yet challenging to access by chemical methods. Now, tyrosine-selective single-atom modifications on proteins have been achieved by C–H functionalization using a rationally designed selenoxide to introduce a versatile selenonium linchpin for further transformations.

The authors identify pathogenic variants in the SMARCA1 gene as the cause of a variable neurodevelopmental disorder. Mouse studies suggest diverse genetic mechanisms related to NURF complex composition mediate the phenotype.

The sorting and assembly machinery (SAM) mediates mitochondrial β-barrel protein folding and membrane insertion. A cryo-EM structure of the yeast SAM complex bound to an early eukaryotic β-barrel intermediate reveals a multipoint guidance mechanism.

Mutations in tRNA processing factors can lead to myelin disorders. This study shows that differentiated oligodendrocytes, cells that make the myelin, are characterized by different tRNA modifications and mRNA decay compared to their precursor cells.

Oat is an important food crop, but the genetic diversity within the gene pool remains unclear. Here, the authors report the analyses of worldwide diversity and population structure of hexaploid oat, and identify signatures of structural rearrangements within the germplasm collection.

DNA-protein crosslinks (DPCs) are toxic DNA lesions which threaten genome stability. Here, the authors develop a method to track the fate of DPCs in cells and identify a role for the SPRTN protease in replication-independent DPC repair.

Bats harbor diverse viruses but it’s less clear how they tolerate infection. Here, by characterizing innate immune responses in bat cells the authors show that IFN-beta signaling resists antagonistic activity by viruses and identify interferon stimulated genes with enhanced antiviral activity.

In this work, the authors describe immunisation of human antibody immune repertoire transgenic mice as a surrogate to define protective human antibody reactivity to clinically diverse, antibiotic resistant Acinetobacter baumannii.

Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathogenic variants in RNU4-2.

Threading of a polypeptide chain is required for knotted proteins to adopt active conformations. A cell-free translation system in conjunction with pulse proteolysis to track folding of trefoil knotted proteins reveal that these knots form spontaneously, but GroEL–GroES enhances the rate of post-translational knot formation.

The rapid access to isotopically labeled organic molecules is a sine qua non condition to support these societally vital areas of research. Here the authors present a solution to access labeled pyridines by a nitrogen isotope exchange reaction based on a Zincke activation strategy.

Dysregulated CD4 T cells have been implicated in autoimmune liver disease, but their phenotypes and origin are still unclear. Here the authors profile circulating, autoreactive CD4 T cells to find transcription signatures similar to tissue-activated, exhausted T cells, thereby hinting a tissue origin for these circulation CD4 T cells.

Targeting histone deacetylases (HDACs) alone has shown limited success in solid tumours. Here, authors report that the HDAC1/2 inhibitor romidepsin confers responsiveness to receptor tyrosine kinase inhibitors, with enhanced therapeutic effects in models of hepatocellular carcinoma, leading to tumour regression and an immune-stimulatory profile.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

KdpD is known as the sensory histidine kinase of two-component system KdpDE that controls the transcription of the kdpFABC genes. Here, the authors show that KdpD acts as atypical serine kinase, which post-translationally regulates KdpFABC.

TatA, B and C act together to translocate folded proteins across bacterial and chloroplast membranes, however the precise mechanism remains unclear. Fröbel and colleagues discover that TatC has unforeseen membrane insertase activity, while TatB prevents premature cleavage before translocation.

The transcriptional regulation of oligodendrocytes has an essential role in myelin formation and maintenance. Here, the authors identify the transcription factor Tfii-i as a regulator of myelin genes expression in the nervous system and show that its loss enhances myelin thickness and nerve conduction.

Cancer cells adapt their metabolism to survive limited nutrient availability. Here, the authors show that in conditions of limited glucose or glutamine availability, pancreatic ductal adenocarcinoma cells can use collagen-derived proline to foster the TCA cycle and allow cell survival bothin vitro and in vivo.

Inhibition of ELOVL6, a fatty acid elongation enzyme, selectively degrades mutant KRAS, disrupts its membrane localization and suppresses tumor growth, revealing a novel vulnerability in KRAS-driven cancers.

The high-resolution cryo-electron microscopy structure of the yeast translocase of the outer mitochondrial membrane reveals key features of mitochondrial protein import that are conserved in all eukaryotes.