Inflammasome activation is essential for host defence against invading pathogens, but is also involved in various forms of inflammatory diseases. The processes that control inflammasome activity are thus important for averting excessive immune responses and tissue damage. Here we show that the deubiquitinase POH1 negatively regulates the immune response triggered by inflammasome activation. POH1 deficiency in macrophages enhances mature IL-1β production without significant alterations in inflammasome priming and ASC-caspase-1 activation. In WT macrophages, POH1 interacts with and deubiquitinates pro-IL-1β by decreasing the K63-linked polyubiquitin chains, as well as decreases the efficacy of pro-IL-1β cleavage. Furthermore, myeloid cell-specific deletion of POH1 aggravates lipopolysaccharide-induced systemic inflammation and alum-induced peritonitis inflammatory responses in vivo. Our study thereby reveals that POH1-mediated deubiquitination of pro-IL-1β is an important regulatory event that restrains inflammatory responses for the maintenance of immune homeostasis.

Much of the world's Li deposits occurs as basinal brines in magmatic orogens, particularly in continental volcanic arcs. However, the exact origin of Li enrichment in arc magmatic systems is not clear. Here, we show that, globally, primitive arc magmas have Li contents and Li/Y ratios similar to mid-ocean ridge basalts, indicating that the subducting slab has limited contribution to Li enrichment in arc magmas. Instead, we find that Li enrichment is enhanced by lower degrees of sub-arc mantle melting and higher extents of intracrustal differentiation. These enrichment effects are favored in arcs with thick crust, which explains why magmatism and differentiation in continental arcs, like the Andes, reach greater Li contents than their island arc counterparts. Weathering of these enriched source rocks mobilizes and transports such Li into the hydrologic system, ultimately developing Li brines with the combination of arid climate and the presence of landlocked extensional basins in thickened orogenic settings.

Constraining thickness and geothermal gradient of Archean continental crust are crucial to understanding geodynamic regimes of the early Earth. Archean crust-sourced tonalitic-trondhjemitic-granodioritic gneisses are ideal lithologies for reconstructing the thermal state of early continental crust. Integrating experimental results with petrochemical data from the Eastern Block of the North China Craton allows us to establish temporal-spatial variations in thickness, geothermal gradient and basal heat flow across the block, which we relate to cooling mantle potential temperature and resultant changing geodynamic regimes from vertical tectonics in the late Mesoarchean (~2.9 Ga) to plate tectonics with hot subduction in the early to late Neoarchean (~2.7-2.5 Ga). Here, we show the transition to a plate tectonic regime plays an important role in the rapid cooling of the mantle, and thickening and strengthening of the lithosphere, which in turn prompted stabilization of the cratonic lithosphere at the end of the Archean.

Oncogenic activation of KRAS and its surrogates is essential for tumour cell proliferation and survival, as well as for the development of protumourigenic microenvironments. Here, we show that the deubiquitinase USP12 is commonly downregulated in the KrasG12D-driven mouse lung tumour and human non-small cell lung cancer owing to the activation of AKT-mTOR signalling. Downregulation of USP12 promotes lung tumour growth and fosters an immunosuppressive microenvironment with increased macrophage recruitment, hypervascularization, and reduced T cell activation. Mechanistically, USP12 downregulation creates a tumour-promoting secretome resulting from insufficient PPM1B deubiquitination that causes NF-κB hyperactivation in tumour cells. Furthermore, USP12 inhibition desensitizes mouse lung tumour cells to anti-PD-1 immunotherapy. Thus, our findings propose a critical component downstream of the oncogenic signalling pathways in the modulation of tumour-immune cell interactions and tumour response to immune checkpoint blockade therapy.

As sequencing depth of chromatin studies continually grows deeper for sensitive profiling of regulatory elements or chromatin spatial structures, aligning and preprocessing of these sequencing data have become the bottleneck for analysis. Here we present Chromap, an ultrafast method for aligning and preprocessing high throughput chromatin profiles. Chromap is comparable to BWA-MEM and Bowtie2 in alignment accuracy and is over 10 times faster than traditional workflows on bulk ChIP-seq/Hi-C profiles and than 10x Genomics' CellRanger v2.0.0 pipeline on single-cell ATAC-seq profiles.

Numerous models explain how cells sense and migrate towards shallow chemoattractant gradients. Studies show that an excitable signal transduction network acts as a pacemaker that controls the cytoskeleton to drive motility. Here we show that this network is required to link stimuli to actin polymerization and chemotactic motility and we distinguish the various models of chemotaxis. First, signalling activity is suppressed towards the low side in a gradient or following removal of uniform chemoattractant. Second, signalling activities display a rapid shut off and a slower adaptation during which responsiveness to subsequent test stimuli decline. Simulations of various models indicate that these properties require coupled adaptive and excitable networks. Adaptation involves a G-protein-independent inhibitor, as stimulation of cells lacking G-protein function suppresses basal activities. The salient features of the coupled networks were observed for different chemoattractants in Dictyostelium and in human neutrophils, suggesting an evolutionarily conserved mechanism for eukaryotic chemotaxis.

Over the Earth's evolutionary history, the style of plate subduction has evolved through time due to the secular cooling of the mantle. While continuous subduction is a typical feature of modern plate tectonics, a stagnant-lid tectonic regime with localized episodic subduction likely characterized the early Earth. The timing of the transition between these two subduction styles bears important insights into Earth's cooling history. Here we apply a statistical analysis to a large geochemical dataset of mafic rocks spanning the last 3.5 Ga, which shows an increasing magnitude of alkali basaltic magmatism beginning at ca. 2.1 Ga. We propose that the rapid rise of continental alkali basalts correlates with an abruptly decreasing degree of mantle melting resulting from the enhanced cooling of the mantle at ca. 2.1 Ga. This might be a consequence of the initiation of continuous subduction, which recycled increasing volumes of cold oceanic crust into the mantle.