RAS signaling gets granular
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Oncogenic RAS induces a distinctive form of non-canonical autophagy mediated by the P38-ULK1-PI4KB axis
Cancer cells with RAS mutations exhibit enhanced autophagy, essential for their proliferation and survival, making it a potential target for therapeutic intervention. However, the regulatory differences between RAS-induced autophagy and physiological autophagy remain poorly understood, complicating the development of cancer-specific anti-autophagy treatments. In this study, we identified a form of non-canonical autophagy induced by oncogenic KRAS expression, termed RAS-induced non-canonical autophagy via ATG8ylation (RINCAA). RINCAA involves distinct autophagic factors compared to those in starvation-induced autophagy and incorporates non-autophagic components, resulting in the formation of non-canonical autophagosomes with multivesicular/multilaminar structures labeled by ATG8 family proteins (e.g., LC3 and GABARAP). We have designated these structures as RAS-induced multivesicular/multilaminar bodies of ATG8ylation (RIMMBA). A notable feature of RINCAA is the substitution of the class III PI3K in canonical autophagy with PI4KB in RINCAA. We identified a regulatory P38-ULK1-PI4KB-WIPI2 signaling cascade governing this process, where ULK1 triggers PI4KB phosphorylation at S256 and T263, initiating PI4P production, ATG8ylation, and non-canonical autophagy. Importantly, elevated PI4KB phosphorylation at S256 and T263 was observed in RAS-mutated cancer cells and colorectal cancer specimens. Inhibition of PI4KB S256 and T263 phosphorylation led to a reduction in RINCAA activity and tumor growth in both xenograft and KPC models of pancreatic cancer, suggesting that targeting ULK1-mediated PI4KB phosphorylation could represent a promising therapeutic strategy for RAS-mutated cancers.
Experimental observation of gapped shear waves and liquid-like to gas-like dynamical crossover in active granular matter
Unlike crystalline solids, liquids lack long-range order, resulting in diffusive shear fluctuations rather than propagating waves. Simulations predict that liquids exhibit a k-gap in wave-vector space, where solid-like transverse waves reappear above this gap. Experimental evidence in classical liquids has been limited, observed only in 2D dusty plasmas. Here, we investigate this phenomenon using active Brownian vibrators and uncover distinct gas-like and liquid-like phases depending on the packing fraction. We measure key properties, including pair correlation functions, mean square displacements, velocity auto-correlation functions, and vibrational density of states. In the liquid-like phase, we confirm the k-gap in transverse excitations, whose size grows as the packing fraction decreases and eventually disappears in the gas phase. Our findings extend the concept of the k-gap to active granular systems and reveal striking parallels with supercritical fluids.
Integration of clinical outcomes and molecular features in extramedullary disease in multiple myeloma
Multiple myeloma (MM) remains incurable despite novel therapeutics. A major contributor to the development of relapsed/refractory and resistant MM is extraosseous extramedullary disease (EMD), whose molecular biology is still not fully understood. We analyzed 528 MM patients who presented to our institution between 2014 and 2021 and who had undergone molecular testing. We defined EMD as organ plasmacytoma distinct from bones and evaluated patients for the development of EMD with the goal of defining their molecular characteristics. Here, we show that RAS/BRAF mutations are likely essential for the development of EMD. Our results also indicate that the underlying reason for the negative outcomes in patients with poor prognostic factors such as duplication 1q and deletion 17p is largely due to the development of EMD. However, the presence of TP53 mutation remains a poor prognostic factor regardless of EMD development. Furthermore, mutation sites of TP53 were different between EMD versus non-EMD patients, with gain-of-function mutations enriched in patients with EMD. Our data highlights distinct molecular abnormalities in patients with EMD and provides potential mechanistic insights for novel therapeutic targets for the future.
Grid-enhancing technologies for clean energy systems
Renewable energy source integration into energy systems can contribute to transmission congestion, which requires time-consuming and capital-intensive upgrades to address. Grid-enhancing technologies (GETs) can increase the capacity of grids with minimal investment, preventing congestion and curtailment of renewable energy. In this Review, we discuss the principles and uses of GETs, which use software and/or hardware to interpret real-time conditions to better use the existing capacity of grid assets. GETs include dynamic line ratings, dynamic transformer ratings, power flow controls, topology optimization, advanced conductor technologies, energy storage systems, and demand response. These GETs can enhance system performance individually, but the deployment of multiple GETs together would greatly increase their effect on the grid capacity and stability by removing multiple capacity bottlenecks in parallel. Infrastructure for real-time data acquisition, transmission and analysis is key to successfully deploying GETs but requires further development and commercialization for broader deployment.
Bacterial toxins induce non-canonical migracytosis to aggravate acute inflammation
Migracytosis is a recently described cellular process that generates and releases membrane-bound pomegranate-like organelles called migrasomes. Migracytosis normally occurs during cell migration, participating in various intercellular biological functions. Here, we report a new type of migracytosis induced by small GTPase-targeting toxins. Unlike classic migracytosis, toxin-induced migrasome formation does not rely on cell migration and thus can occur in both mobile and immobile cells. Such non-canonical migracytosis allows the cells to promptly respond to microbial stimuli such as bacterial toxins and effectors and release informative cellular contents in bulk. We demonstrated that C. difficile TcdB3 induces liver endothelial cells and Kupffer cells to produce migrasomes in vivo. Moreover, the migracytosis-defective Tspan9‒/‒ mice show less acute inflammation and lower lethality rate in the toxin challenge assay. Therefore, we propose that the non-canonical migracytosis acts as a new mechanism for mammalian species to sense and exacerbate early immune response upon microbial infections.
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