The structures of natural RNAs remain poorly characterized and may hold numerous surprises1-4. Here we report three-dimensional structures of three large ornate bacterial RNAs using cryo-electron microscopy (cryo-EM). GOLLD (Giant, Ornate, Lake- and Lactobacillales-Derived), ROOL (Rumen-Originating, Ornate, Large) and OLE (Ornate Large Extremophilic) RNAs form homo-oligomeric complexes whose stoichiometries are retained at lower concentrations than measured in cells. OLE RNA forms a dimeric complex with long co-axial pipes spanning two monomers. Both GOLLD and ROOL form distinct RNA-only multimeric nanocages with diameters larger than the ribosome, each empty except for a disordered loop. Extensive intramolecular and intermolecular A-minor interactions, kissing loops, an unusual A-A helix and other interactions stabilize the three complexes. Sequence covariation analysis of these large RNAs reveals evolutionary conservation of intermolecular interactions, supporting the biological importance of large, ornate RNA quaternary structures that can assemble without any involvement of proteins.

Chronic stress response activation impairs cell survival and causes devastating degenerative diseases1-3. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase silencing factor of the integrated stress response (SIFI), to terminate stress response signalling and ensure cellular homeostasis4. How a silencing factor can sense stress across cellular scales to elicit timely stress response inactivation is poorly understood. Here we combine cryo-electron microscopy analysis of endogenous SIFI with AlphaFold modelling and biochemical studies to report the structural and mechanistic basis of the silencing of the integrated stress response. SIFI detects both stress indicators and stress response components through flexible domains within an easily accessible scaffold, before building linkage-specific ubiquitin chains at separate, sterically restricted elongation modules. Ubiquitin handover by a ubiquitin-like domain couples versatile substrate modification to linkage-specific ubiquitin polymer formation. Stress response silencing therefore exploits a catalytic mechanism that is geared towards processing many diverse proteins and therefore allows a single enzyme to monitor and, if needed, modulate a complex cellular state.

Legume roots secure nitrogen by forming a symbiosis with soil rhizobia but remain resistant to pathogenic bacteria1-4. How this tolerance to rhizobia is achieved without compromising plant immunity is largely unknown. Here we identify the cytoplasmic kinase MtLICK1/2, which interacts with nodulation factor receptor MtLYK3 to drive symbiotic signalling and suppress plant immunity. Rhizobial infection and nodule development are defective in Mtlick1/2, phenocopying the Mtlyk3-1 mutant. MtLICK1/2 and MtLYK3 undergo reciprocal transphosphorylation during rhizobial symbiosis. Phosphorylated MtLYK3 activates the receptor-like kinase MtDMI2 to stimulate symbiotic signalling. MtLICK1/2 is activated in the rhizobial infection area to suppress plant immunity. Thus, MtLICK1/2 and MtLYK3 together amplify symbiotic signalling and dampen host immunity to enable legume-rhizobium symbiosis.

Alcohol use disorder (AUD) is highly heritable and burdensome worldwide. Genome-wide association studies (GWASs) can provide new evidence regarding the aetiology of AUD. We report a multi-ancestry GWAS focusing on a narrow AUD phenotype, using novel statistical tools in a total sample of 1,041,450 individuals [102,079 cases; European, 75,583; African, 20,689 (mostly African-American); Hispanic American, 3,449; East Asian, 2,254; South Asian, 104; descent]. Cross-ancestry functional analyses were performed with European and African samples. Thirty-seven genome-wide significant loci (105 variants) were identified, of which seven were novel for AUD and six for other alcohol phenotypes. Loci were mapped to genes, which show altered expression in brain regions relevant for AUD (striatum, hypothalamus, and prefrontal cortex) and encode potential drug targets (GABAergic, dopaminergic and serotonergic neurons). African-specific analysis yielded a unique pattern of immune-related gene sets. Polygenic overlap and positive genetic correlations showed extensive shared genetic architecture between AUD and both mental and general medical phenotypes, suggesting they are not only complications of alcohol use but also share genetic liability with AUD. Leveraging a cross-ancestry approach allowed identification of novel genetic loci for AUD and underscores the value of multi-ancestry genetic studies. These findings advance our understanding of AUD risk and clinically-relevant comorbidities.