Condensation of ZFP207 and U1 snRNP promotes spliceosome assembly
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Structural insights into spliceosome fidelity: DHX35–GPATCH1- mediated rejection of aberrant splicing substrates
The spliceosome, a highly dynamic macromolecular assembly, catalyzes the precise removal of introns from pre-mRNAs. Recent studies have provided comprehensive structural insights into the step-wise assembly, catalytic splicing and final disassembly of the spliceosome. However, the molecular details of how the spliceosome recognizes and rejects suboptimal splicing substrates remained unclear. Here, we show cryo-electron microscopy structures of spliceosomal quality control complexes from a thermophilic eukaryote, Chaetomium thermophilum. The spliceosomes, henceforth termed B*Q, are stalled at a catalytically activated state but prior to the first splicing reaction due to an aberrant 5’ splice site conformation. This state is recognized by G-patch protein GPATCH1, which is docked onto PRP8-EN and -RH domains and has recruited the cognate DHX35 helicase to its U2 snRNA substrate. In B*Q, DHX35 has dissociated the U2/branch site helix, while the disassembly helicase DHX15 is docked close to its U6 RNA 3’-end substrate. Our work thus provides mechanistic insights into the concerted action of two spliceosomal helicases in maintaining splicing fidelity by priming spliceosomes that are bound to aberrant splice substrates for disassembly.
Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching
Solid stress, originating from rigid and elastic components of extracellular matrix and cells, is a typical physical hallmark of tumors. Mounting evidence indicates that elevated solid stress drives metastasis and affects prognosis. However, the molecular mechanism of how cancer cells sense solid stress, thereby exacerbating malignancy, remains elusive. In this study, our clinical data suggest that elevated stress in metastatic solid tumors is highly associated with the expression of cytoskeleton-associated protein 4 (CKAP4). Intriguingly, CKAP4, as a sensitive intracellular mechanosensor, responds specifically to solid stress in a subset of studied tumor micro-environmental elements through liquid–liquid phase separation. These micron-scaled CKAP4 puncta adhere tightly onto microtubules and dramatically reorchestrate their curvature and branching to enhance cell spreading, which, as a result, boosts cancer cell motility and facilitates distant metastasis in vivo. Mechanistically, the intrinsically disordered region 1 (IDR1) of CKAP4 binds to microtubules, while IDR2 governs phase separation due to the Cav1.2-dependent calcium influx, which collectively remodels microtubules. These findings reveal an unprecedented mechanism of how cancer cells sense solid stress for cancer malignancy and bridge the gap between cancer physics and cancer cell biology.
Golgi condensation causes intestinal lipid accumulation through HIF-1α-mediated GM130 ubiquitination by NEDD4
The breakdown of Golgi proteins disrupts lipid trafficking, leading to lipid accumulation in the small intestine. However, the causal mechanism of the effects of Golgi protein degradation on the Golgi structure related to lipid trafficking in the small intestine remains unknown. Here we find that Golgi protein degradation occurs under hypoxic conditions in high-fat-diet-fed mice. Hypoxia-induced degradation promotes structural changes in the Golgi apparatus, termed ‘Golgi condensation’. In addition, hypoxia-inducible factor 1α (HIF-1α) activation enhances Golgi condensation through the ubiquitination and degradation of Golgi matrix protein 130 (GM130), which is facilitated by neural precursor cell expressed developmentally downregulated protein 4 (NEDD4). Golgi condensation upon exposure to hypoxia promotes lipid accumulation, apolipoprotein A1 retention and decreased chylomicron secretion in the intestinal epithelium. Golgi condensation and lipid accumulation induced by GM130 depletion are reversed by exogenous GM130 induction in the intestinal epithelium. Inhibition of either HIF-1α or NEDD4 protects against GM130 degradation and, thereby, rescues cells from Golgi condensation, which further increases apolipoprotein A1 secretion and lipid accumulation both in vivo and in vitro. Furthermore, the HIF-1α inhibitor PX-478 prevents Golgi condensation, which decreases lipid accumulation and promotes high-density lipoprotein secretion in high-fat-diet-fed mice. Overall, our results suggest that Golgi condensation plays a key role in lipid trafficking in the small intestine through the HIF-1α- and NEDD4-mediated degradation of GM130, and these findings highlight the possibility that the prevention of structural modifications in the Golgi apparatus can ameliorate intestinal lipid accumulation in obese individuals.
Solar-driven interfacial evaporation technologies for food, energy and water
Solar-driven interfacial evaporation technologies use solar energy to heat materials that drive water evaporation. These technologies are versatile and do not require electricity, which enables their potential application across the food, energy and water nexus. In this Review, we assess the potential of solar-driven interfacial evaporation technologies in food, energy and clean-water production, in wastewater treatment, and in resource recovery. Interfacial evaporation technologies can produce up to 5.3 l m–2 h−1 of drinking water using sunlight as the energy source. Systems designed for food production in coastal regions desalinate water to irrigate crops or wash contaminated soils. Technologies are being developed to simultaneously produce both clean energy and water through interfacial evaporation and have reached up to 204 W m–2 for electricity and 2.5 l m–2 h–1 for water in separate systems. Other solar evaporation approaches or combinations of approaches could potentially use the full solar spectrum to generate multiple products (such as water, food, electricity, heating or cooling, and/or fuels). In the future, solar evaporation technologies could aid in food, energy and water provision in low-resource or rural settings that lack reliable access to these essentials, but the systems must first undergo rigorous, scaled-up field testing to understand their performance, stability and competitiveness.
Intracellular assembly of supramolecular peptide nanostructures controlled by visible light
The complex dynamics of synthetic supramolecular systems in living cellular environments impede the correlation between the transient hierarchical species and their biological functions. Achieving this correlation demands a breakthrough that combines the precise control of supramolecular events at discrete time points via synthetic chemistry with their real-time visualization in native cells. In the present study, we reported two peptide sequences that undergo visible light-induced molecular and supramolecular transformations to form various assembly species in cells. In contrast to endogenous stimulus-responsive assembly, the proposed photochemistry enables full control over the photolysis reaction where the monomer generation and local concentration regulate the subsequent assembly kinetics. Phasor-fluorescence lifetime imaging traced the formation of various assembly states in cells associated with monomer activation and consumption, whereas correlative light-electron microscopy revealed the intracellular nanofibres formed. The temporally resolved assembly process shows that the emergence of cytotoxicity correlates with the accumulation of oligomers beyond the cellular efflux threshold.
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