Articles

An examination of metabolic changes during B cell differentiation reveals that germinal center B cells selectively upregulate methylenetetrahydrofolate dehydrogenase 2-mediated one-carbon metabolism, resulting in increased availability of nucleotide precursors and antioxidants.

Zhu et al. found that cytidine triphosphate usage in the Kennedy pathway for phospholipid synthesis influences nucleotide metabolism and redox balance. Phospholipid synthesis acts as an integrative defense mechanism to sense and combat oxidative stress.

β-Lactam antibiotics are detected by the sensor domain of BlaR in methicillin-resistant Staphylococcus aureus. A class of inhibitors has been developed that targets this sensor domain and prevents downstream activation of the antibiotic response pathway.

Soapwort (Saponaria officinalis) is a rich reservoir of triterpenoid glycosides that often have important pharmaceutical, nutraceutical and agronomical potential. Here, the authors elucidate the complete biosynthetic pathway of saponarioside B, a major saponin constituent in soapwort.

SMAD ubiquitylation regulatory factor 1 (Smurf1) was identified as a critical activator of the phosphoinositide 3-kinase (PI3K)–Akt pathway by promoting phosphoinositide-dependent protein kinase 1 (PDK1) neddylation and cytoplasmic complex of PDK1 assembled with Smurf1 and SETDB1 (cCOMPASS) assembly. Smurf1-antagonizing repressor of tumor 1 (SMART1), a highly selective degrader for Smurf1, was developed and suppressed the tumor growth of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant colorectal cancer.

Hybrids of macrolides and quinolones, called macrolones, can overcome macrolide-induced resistance through new interactions between the quinolone moiety and the ribosome and can concurrently inhibit both ribosome and DNA gyrase targets.

Using a combination of antibody- and LC–MS/MS-based methods, Zhang et al. reveal lysine l-lactylation as the key lactylation isomer in cellular histones, responding dynamically to glycolysis and positively correlating with lactyl-CoA levels, providing insights into the Warburg effect.

Protein misfolding can spread from one molecule to another in infectious prion diseases. The propagation of protein misfolding has been directly observed in single protein molecules. These results showed that pathogenic mutants of the protein superoxide dismutase-1 (SOD1), which causes familial amyotrophic lateral sclerosis, imprint their misfolding onto native wild-type molecules.

González-Delgado et al. developed retron-based editors termed multitrons, which can modify multiple sites on a single genome simultaneously. This technology is compatible with recombineering in prokaryotes and CRISPR editing in eukaryotes with applications in molecular recording, genome minimization and metabolic engineering.

Time-resolved synthesis of target proteins via proximity-triggered protein trans-splicing has now been shown to enable the activation of a diverse set of proteins upon the addition or removal of control elements. This temporal precision allows for monitoring distinct phases in cellular signaling and unveiling the molecular connections of oncofusion kinases, including DNAJ–PKAc.

By engineering a tiny OgeuIscB–ωRNA system and tethering DNA-binding protein Sso7d, the authors developed robust miniature base editors SIminiBEs, which achieved robust C-to-T and A-to-G base transitions with a broad targeting range.

The ICP1 (International Center for Diarrheal Disease Research, Bangladesh cholera phage 1) clustered regularly interspaced short palindromic repeats (CRISPR)–Cas system, which lacks the helical bundle domain in Cas8f, uses Cas1 to mediate the interference stage by connecting Cas2/3 to the DNA-bound CRISPR-associated complex for antiviral defense (Cascade).

Through rational protein engineering and structure-guided ωRNA engineering, the ωRNA-guided endonuclease IscB system was developed into a highly efficient and compact genome-editing tool.

Yan and Tang developed a CRISPR-based RNA-editing approach called DECOR by fusing a Cas13 variant to an evolved E. coli tRNA adenosine deaminase, TadA8e, enabling adenosine-to-inosine editing to specified sites in the human transcriptome.

RNA-based genetic regulation has been used to control protein translation in synthetic cells in response to the external temperature. RNA thermometers enable in situ protein expression above permissive temperatures. Controlled expression of the membrane pore α-hemolysin allows small-molecule cargo to be released in a temperature-dependent manner.

Lee, Barone et al. engineered a mutant form of LSD1, Y391K, which renders the nucleosome demethylase activity of LSD1 insensitive to Lys14 acetylation of histone H3, providing a useful tool to illuminate the functional consequences of disconnecting histone modification crosstalk.

Basu et al. report a clustered regularly interspaced short palindromic repeats (CRISPR)-based transcriptional activation screen method for the discovery of E3 ligases suitable for targeted protein degradation and identify the E3 ligase F-box protein 22 capable of promoting ligand-induced degradation of multiple proteins.

Nie et al. describe a mechanism underlying the degradation of the histone methyltransferase NSD2 through the recruitment of FBXO22 E3 ligase, providing a chemical probe for NSD2 function study and targeted protein degradation.

Total in vitro biosynthesis can reveal unusual pathways evolved by nature to produce natural products. Here the authors report on enzymatic cascades, comprising a cryptic methylation sequence, efficiently delivering β-lactone-containing peptide proteasome inhibitors with promising anticancer activity.

The enzymes that link bacterial capsule polymers to the outermembrane glycolipids, termed transition transferases, are identified, enabling reconstruction of the entire capsule biosynthesis pathway.