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Growing cells coordinate protein translation with metabolic rates. Central to this coordination is ribosome production. Ribosomes drive cell growth, but translation of ribosomal proteins competes with production of non-ribosomal proteins. Theory shows that cell growth is maximized when all expressed ribosomes are constantly translating. To examine whether budding yeast function at this limit of full ribosomal usage, we profiled the proteomes of cells growing in different environments. We find that cells produce excess ribosomal proteins, amounting to a constant ≈8% of the proteome. Accordingly, ≈25% of ribosomal proteins expressed in rapidly growing cells does not contribute to translation. Further, this fraction increases as growth rate decreases and these excess ribosomal proteins are employed when translation demands unexpectedly increase. We suggest that steadily growing cells prepare for conditions that demand increased translation by producing excess ribosomes, at the expense of lower steady-state growth rate.

Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function. This study demonstrates the activation of a STAT3-independent healing pathway in response to mucosal injury which involves the co-receptor for IL-6 cytokines gp130 and downstream effectors Src, Yes, YAP and Notch. Beneficial effects of inflammation As well as activating innate and adaptive immunity, inflammation triggers tissue repair and regeneration through mechanisms that are largely unknown. This study demonstrates the activation of a STAT3-independent healing pathway in a mouse model of experimental colitis through a process involving gp130 (a co-receptor for interleukin-6 family cytokines) and the downstream effectors Src, Yes, YAP and Notch.

The intestinal epithelium has a high rate of turnover, and dysregulation of pathways that regulate regeneration can lead to tumor development; however, the negative regulators of oncogenic events in the intestinal epithelium are not fully understood. Here we identified a feedback loop between the epidermal growth factor receptor (EGFR), a known mediator of proliferation, and the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), in intestinal epithelial cells (IECs). We found that TRPV1 was expressed by IECs and was intrinsically activated upon EGFR stimulation. Subsequently, TRPV1 activation inhibited EGFR-induced epithelial cell proliferation via activation of Ca2+/calpain and resulting activation of protein tyrosine phosphatase 1B (PTP1B). In a murine model of multiple intestinal neoplasia (Apc(Min/+) mice), TRPV1 deficiency increased adenoma formation, and treatment of these animals with an EGFR kinase inhibitor reversed protumorigenic phenotypes, supporting a functional association between TRPV1 and EGFR signaling in IECs. Administration of a TRPV1 agonist suppressed intestinal tumorigenesis in Apc(Min/+) mice, similar to--as well as in conjunction with--a cyclooxygenase-2 (COX-2) inhibitor, which suggests that targeting both TRPV1 and COX-2 has potential as a therapeutic approach for tumor prevention. Our findings implicate TRPV1 as a regulator of growth factor signaling in the intestinal epithelium through activation of PTP1B and subsequent suppression of intestinal tumorigenesis.

The ERK1/2 MAPK signalling module integrates extracellular cues that induce proliferation and differentiation of epithelial lineages, and is an established oncogenic driver, particularly in the intestine. However, the interrelation of the ERK1/2 module relative to other signalling pathways in intestinal epithelial cells and colorectal cancer (CRC) is unclear. Here we show that loss of Erk1 / 2 in intestinal epithelial cells results in defects in nutrient absorption, epithelial cell migration and secretory cell differentiation. However, intestinal epithelial cell proliferation is not impeded, implying compensatory mechanisms. Genetic deletion of Erk1/2 or pharmacological targeting of MEK1/2 results in supraphysiological activity of the ERK5 pathway. Furthermore, targeting both pathways causes a more effective suppression of cell proliferation in murine intestinal organoids and human CRC lines. These results suggest that ERK5 provides a common bypass route in intestinal epithelial cells, which rescues cell proliferation upon abrogation of ERK1/2 signalling, with therapeutic implications in CRC. It is unclear how the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways interact with other signals in intestinal epithelial cells. Here, the authors show that upon loss of Erk1/2 , or pharmacological inhibition of MEK1/2, the ERK5 pathway is upregulated to maintain epithelial cell proliferation.

Experimental colitis is mediated by inflammatory or dysregulated immune responses to microbial factors of the gastrointestinal tract. In this study we observed that administration of Toll-like receptor 9 (TLR9) agonists suppressed the severity of experimental colitis in RAG1-/- but not in SCID mice. This differential responsiveness between phenotypically similar but genetically distinct animals was related to a partial blockade in TLR9 signaling and defective production of type I IFN (i.e., IFN-alpha/beta) in SCID mice upon TLR9 stimulation. The addition of neutralization antibodies against type I IFN abolished the antiinflammatory effects induced by TLR9 agonists, whereas the administration of recombinant IFN-beta mimicked the antiinflammatory effects induced by TLR9 agonists in this model. Furthermore, mice deficient in the IFN-alpha/beta receptor exhibited more severe colitis than wild-type mice did upon induction of experimental colitis. These results indicate that TLR9-triggered type I IFN has antiinflammatory functions in colitis. They also underscore the important protective role of type I IFN in intestinal homeostasis and suggest that strategies to modulate innate immunity may be of therapeutic value for the treatment of intestinal inflammatory conditions.

Cyclic AMP (cAMP) is involved in many biological processes but little is known regarding its role in shaping immunity. Here we show that cAMP-PKA-CREB signaling (a pattern recognition receptor [PRR]-independent mechanism) regulates conventional type-2 Dendritic Cells (cDC2s) in mice and reprograms their Th17-inducing properties via repression of IRF4 and KLF4, transcription factors essential for cDC2-mediated Th2 induction. In mice, genetic loss of IRF4 phenocopies the effects of cAMP on Th17 induction and restoration of IRF4 prevents the cAMP effect. Moreover, curdlan, a PRR-dependent microbial product, activates CREB and represses IRF4 and KLF4, resulting in a pro-Th17 phenotype of cDC2s. These in vitro and in vivo results define a novel signaling pathway by which cDC2s display plasticity and provide a new molecular basis for the classification of novel cDC2 and cDC17 subsets. The findings also reveal that repressing IRF4 and KLF4 pathway can be harnessed for immuno-regulation.

Loss of tumor suppressor adenomatous polyposis coli (APC) activates β-catenin to initiate colorectal tumorigenesis. However, β-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1.

House dust mite (HDM) is a common environmental aeroallergen strongly associated with asthma and chronic airway inflammation. While HDM exposure is known to induce T helper 2 (Th2)-mediated eosinophilic inflammation, its chronic effects on interleukin-1β (IL-1β)-associated neutrophilic inflammation remain poorly understood. This study used single-cell RNA sequencing (scRNA-seq) to investigate how chronic HDM exposure remodels the murine lung immune microenvironment, with a focus on the role of IL-1β in shaping HDM-driven immune responses. Wild-type and -deficient mice on a C57BL/6 background were subjected to chronic HDM exposure over a 5-week period, and scRNA-seq was performed to characterize changes in the lung immune landscape. To enhance resolution of specific cell populations and better define their functional states, we performed subclustering, followed by pathway enrichment and transcription factor activity analyses. To account for endotoxin-dependent variability in HDM extracts, scRNA-seq was conducted using a low-lipopolysaccharide (LPS) HDM extract, while validation studies (histopathology, RT-qPCR, ELISA, and immunofluorescence) were performed using a high-LPS HDM extract. Our analysis demonstrates that chronic HDM exposure promotes the recruitment and activation of diverse immune cell populations in the lungs, including neutrophils, M2-polarized macrophages, B-2 (follicular) B cells, and multiple subsets of regulatory and effector CD4⁺ T cells. These populations contribute differently to the development or resolution of chronic lung inflammation through IL-1β-dependent and -independent mechanisms. scRNA-seq indicated that IL-1β signaling is critical for sustaining neutrophil and Th17 responses, whereas deficiency promotes Th2-skewed polarization. Validation experiments revealed that these effects are influenced by the endotoxin content of HDM extracts, which can override genotype-dependent effects. These findings demonstrate that chronic HDM exposure profoundly remodels the lung immune microenvironment through IL-1β-dependent and -independent mechanisms. The effects are context-dependent and modulated by the endotoxin content of HDM extracts, highlighting the complex immunomodulatory effects of HDM in inducing chronic lung inflammation.

Genome-encoded microRNAs (miRNAs) provide a posttranscriptional regulatory layer that controls the differentiation and function of various cellular systems, including hematopoietic cells. miR-142 is one of the most prevalently expressed miRNAs within the hematopoietic lineage. To address the in vivo functions of miR-142, we utilized a novel reporter and a loss-of-function mouse allele that we have recently generated. In this study, we show that miR-142 is broadly expressed in the adult hematopoietic system. Our data further reveal that miR-142 is critical for megakaryopoiesis. Genetic ablation of miR-142 caused impaired megakaryocyte maturation, inhibition of polyploidization, abnormal proplatelet formation, and thrombocytopenia. Finally, we characterized a network of miR-142-3p targets which collectively control actin filament homeostasis, thereby ensuring proper execution of actin-dependent proplatelet formation. Our study reveals a pivotal role for miR-142 activity in megakaryocyte maturation and function, and demonstrates a critical contribution of a single miRNA in orchestrating cytoskeletal dynamics and normal hemostasis. DNA carries all the information needed for life. This includes the codes required for making proteins, as well as instructions on when, where, and how much of these proteins need to be produced. There are a number of ways by which cells control protein manufacturing, one of which is based on small RNAs called microRNAs. Before proteins are assembled, the DNA molecule is copied into a temporary replica dubbed messenger RNA. microRNAs are able to recognize specific messenger RNA molecules and block protein production. microRNAs serve a very important regulatory role in our bodies and are involved in virtually all cellular processes, including the production of all classes of blood and immune cells. Platelets seal injuries and prevent excessive bleeding by creating a clot at the location of a wound. Platelets are produced in huge cellular factories called megakaryocytes, which need to have a flexible and dynamic internal skeleton or cytoskeleton to produce the platelets. Chapnik et al. focus on one specific microRNA gene, which is vital for the production and the function of several classes of blood and immune cells. Chapnik et al. created a mouse model that does not produce one specific microRNA—miR-142—and found that mutant mice produced fewer platelets than normal mice. Although one possible explanation for this is that the mutant mice also had fewer megakaryocytes than normal, Chapnik et al. unexpectedly found that the number of megakaryocytes was in fact higher. However, these megakaryocytes do not reach functional maturity, which is required for platelet production. Many of the megakaryocytes made by the mutant mice were also smaller than normal and had an unusual cytoskeleton. Using a genomic approach and molecular tools, Chapnik et al. show that miR-142 affects the production of several of the proteins responsible for the dynamic flexibility of the cytoskeleton in mature megakaryocytes. Therefore, a single microRNA can target multiple different proteins that coordinate the same pathway in the cells that are critical for clotting and hence for human health. miR-142 has also been suggested to have important functions in blood stem cells and in blood cancer (leukemia). Therefore, the new mouse model could be used to investigate many other facets of the blood and immune system. Further research could also focus on whether the same cytoskeletal network is in charge of miR-142 activity in other blood cells, or if miR-142 silences different targets in different cells.

Chronic decreases in the second messenger cyclic AMP (cAMP) occur in numerous settings, but how cells compensate for such decreases is unknown. We have used a unique system—murine dendritic cells (DCs) with a DC-selective depletion of the heterotrimeric GTP binding protein Gα s —to address this issue. These mice spontaneously develop Th2-allergic asthma and their DCs have persistently lower cAMP levels. We found that phosphodiesterase 4B (PDE4B) is the primary phosphodiesterase expressed in DCs and that its expression is preferentially decreased in Gα s -depleted DCs. PDE4B expression is dynamic, falling and rising in a protein kinase A-dependent manner with decreased and increased cAMP concentrations, respectively. Treatment of DCs that drive enhanced Th2 immunity with a PDE4B inhibitor ameliorated DC-induced helper T cell response. We conclude that PDE4B is a homeostatic regulator of cellular cAMP concentrations in DCs and may be a target for treating Th2-allergic asthma and other settings with low cellular cAMP concentrations.