Cell Death and Differentiation最新文献

The adult mammalian heart is characterized by post-mitotic polyploid cardiomyocytes (CMs). Understanding how CMs regulate cell cycle exit and polyploidy can help developing new heart regenerative therapies. Here, we uncover that the PIDDosome, a multi-protein complex activating the endopeptidase Caspase-2, helps to implement a CM-specific differentiation program that limits ploidy during postnatal heart development. DNA content analyses show that cell-autonomous PIDDosome loss causes an increase in nuclear and cellular CM ploidy. Increased ploidy does not affect cardiac structure nor function in early adulthood, but correlates with a modest reduction in cardiac performance in aged mice. PIDDosome-imposed polyploidy control commences at postnatal day 7 (P7), reaching a plateau by P14. PIDDosome activation requires ANKRD26, targeting PIDD1 to mother centrioles. Opposite to prior observations in liver development, the PIDDosome limits CM polyploidization in a p53-independent manner but reliant on induction of p21/Cdkn1a, a notion supported by nuclear RNA sequencing and genetic deletion experiments. Our results provide new insights how proliferation of polyploid CMs is restricted during postnatal heart development.

Ribosomal RNA Modifying Proteins (RRMPs) are integral to ribosome biogenesis, executing post-transcriptional modifications that influence translation fidelity and efficiency. Dysregulation of RRMPs has been increasingly implicated in cancer progression, yet their collective role across malignancies remains largely unexplored. Here, we performed a multi-omics analysis of 22 RRMPs across diverse cancer types using The Cancer Genome Atlas, the Molecular Taxonomy of Breast Cancer International Consortium, and additional high-throughput datasets. Our analysis revealed widespread genomic alterations and transcriptional dysregulation of RRMPs across malignancies, with distinct expression patterns in breast cancer subtypes. Notably, Triple-Negative Breast Cancer (TNBC) exhibited the highest RRMPs enrichment, which correlated with increased genomic instability including elevated tumor mutational burden and aneuploidy scores, and poor survival outcomes. Among the RRMPs, tRNA methyltransferase activator subunit 11-2 (TRMT112) emerged as a key regulator of tumor progression. Functional assays demonstrated that TRMT112 knockdown in TNBC cells significantly reduced proliferation, migration, invasion, and metastatic potential, whereas its overexpression enhanced these tumorigenic properties. Polysome profiling and RNA sequencing of actively translated transcripts revealed that TRMT112 reprograms the translational landscape by promoting pro-metastatic and stromal remodeling pathways while suppressing immune-related processes. In vivo studies using an orthotopic breast cancer model further confirmed that TRMT112 depletion impairs tumor growth and reduces metastatic burden. Collectively, our findings establish RRMPs as critical modulators of cancer progression and identify TRMT112 as a key driver of aggressive phenotypes in TNBC. The dysregulation of TRMT112 across breast cancer subtypes highlights its potential as both a prognostic biomarker and a therapeutic target. These insights provide a mechanistic foundation for future interventions aimed at targeting TRMT112-driven translational programs in aggressive breast cancer.

Inhibition of endothelial cell (EC) death is essential for normal angiogenesis. The E3 ubiquitin ligase HOIP, the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC), is particularly important for EC survival during embryogenesis. The stability of HOIP is critical for LUBAC function. However, the mechanisms underlying the regulation of HOIP stability are largely unknown. Here, we uncovered a novel role of G protein pathway suppressor 2 (GPS2) in regulating EC survival and embryonic vascularization via control of HOIP stability. EC-specific GPS2 deletion mice (Gps2^ECKO) are embryonic lethal at embryonic day 16.5 (E16.5) due to defective vascularization. Deficiency of GPS2 in ECs results in aberrant TNFR1-mediated cell death. TNFR1 deletion in Gps2^ECKO mice restores normal vascularization and rescues embryonic lethality. At the molecular level, GPS2 binds to the NZF domain of HOIP and inhibits K48-linked polyubiquitination of HOIP at K579, K737, and K988 residues. GPS2 prevents HOIP proteasomal degradation and thus maintains LUBAC stability and activity. GPS2 deficiency in ECs leads to HOIP degradation and LUBAC instability, which in turn attenuates TNF-induced NF-κB activation and exacerbates the formation of the cell-death-inducing complex-II, ultimately increasing EC death. Overall, our data demonstrate that GPS2 is required for maintaining vascular integrity during embryogenesis by inhibiting TNFR1-mediated EC death via stabilizing HOIP.

Lineage plasticity in non-small cell lung cancer (NSCLC) drives resistance to tyrosine kinase inhibitor (TKI) therapies, yet the epigenetic drivers of this phenotypic transition remain poorly defined. Here, we identify loss of the histone methyltransferase KMT2D as a critical event that disrupts adenocarcinoma lineage fidelity and promotes squamous transition. KMT2D expression is markedly reduced in TKI-resistant NSCLC with squamous-like features, and its mutation correlates with elevated squamous lineage markers and poorer clinical outcomes. Mechanistically, KMT2D loss triggers global transcriptional and epigenomic reprogramming, upregulating squamous master regulators such as ΔNp63 and SOX2. CRISPR-based screening reveals that KMT2D-deficient tumors are preferentially dependent on AURKA to maintain squamous identity and cell proliferation. Notably, loss of KMT2D enhances AURKA stability and activity by disrupting its interaction with the E3 ligase FBXW7, resulting in reduced ubiquitination and prolonged AURKA signaling. Pharmacologic inhibition of AURKA abrogates squamous features and suppresses tumor growth in patient-derived organoids, xenografts, and orthotopic models, with KMT2D-deficient tumors exhibiting heightened sensitivity. These findings uncover that KMT2D alteration drives chromatin reprogramming that facilitates adeno-to-squamous transition and identifies AURKA as a lineage-specific vulnerability, providing a precision strategy to overcome TKI resistance.Statement of significanceOur study identifies KMT2D loss as a key event of lineage switch that promotes adeno-to-squamous transition and TKI resistance in NSCLC. This epigenetic shift renders tumors dependent on AURKA, revealing a novel therapeutic target to counteract drug resistance and improve treatment outcomes.

Skin homeostasis depends on interactions between epithelial cells and the microbiome mediated by molecular and biochemical factors. Perturbations of this interplay are linked to inflammatory disorders, including wound healing and cancer. While research has mainly illuminated shifts in microbial community composition, novel computational approaches are starting to reveal the host-microbe functional interactome in the cutaneous ecosystem. In this review, we specifically focus on known molecular and metabolic mechanisms linking skin epithelial cells and microorganisms in health and disease. Additionally, we summarise computational tools available to investigate these interactions integrating omics data. Furthermore, we present potential applications of this functional crosstalk to advance therapies targeting skin pathologies. Finally, we propose a comparative interactomics approach to envision the existence of ecological memories in the skin ecosystem, in parallel with the one described in the gut, hypothesising a link between epithelial and microbial memories in barrier tissues.

Sepsis, a devastating microbe-induced inflammatory response, culminates in multi-organ dysfunction, with pyroptosis mediated by the non-canonical inflammasome being a pivotal factor. The mouse Caspase-11, central to this pathway, is directly activated by cytoplasmic lipopolysaccharide (LPS). Although ubiquitination is known to tightly regulate the inflammatory response in pyroptosis, its role in modulating the non-canonical inflammasome remains enigmatic. In this study, we unveil that the E3 ubiquitin ligase Smurf1 is a critical negative regulator of the non-canonical inflammasome pathway. Smurf1 orchestrates K48-linked polyubiquitination of Caspase-11 at K245 and K247 residues, leading to its degradation via the 26S proteasome. This process is further amplified by ERK phosphorylation of Smurf1 at the S148 site. In parallel, Caspase-11 modulates Smurf1 protein content through cleavage. Notably, macrophage-specific Smurf1 deficiency exacerbates sepsis-induced mortality in mice, attributed to the hyperactivation of the non-canonical inflammasome. Conversely, targeted supplementation of Smurf1 in macrophages mitigates the high mortality and inflammatory response associated with sepsis. Thus, Smurf1 emerges as a key player in modulating the activation of the non-canonical inflammasome in response to Gram-negative bacterial infections.

Persisters are a rare sub-population of tumor cells that survive anti-cancer therapy and are thought to be a major cause of recurrence. These cells have been identified following both drug- and immune-therapy but are generally considered to be distinct entities. Since both pharmacological agents and immune cells often kill via apoptosis, we tested a hypothesis that both types of cells survive based on reduced mitochondrial apoptotic sensitivity, which in turn would yield a similar and reciprocal multi-agent resistant phenotype. Supporting this hypothesis, we indeed observed that IPCs acquired a reduced sensitivity to multiple drug classes and radiotherapy, suggesting non-immune mechanisms are important in the survival of cancer cells after immunotherapy. Likewise, DTPs developed not only a reduced sensitivity to multiple drug classes and radiotherapy, but also acquired a reduced sensitivity to T cell killing. Both IPCs and DTPs developed decreased sensitivity to mitochondrial apoptosis. A sub-population of IPCs downregulated antigen and upregulated PD-L1. Intriguingly, in the IPCs that didn't employ these mechanisms of resistance, a greater decrease in sensitivity to mitochondrial apoptosis was observed, suggesting that the presence or absence of a resistance mechanism can exert selective pressures over the emergence of others. Targeting anti-apoptotic dependencies in persisters increased sensitivity to chemotherapy or CAR T therapy. These results suggest that common biological mechanisms underly survival of persisters, whether derived from immune or drug therapy, and offer an explanation for the acquired cross-resistance to these two types of therapies often observed in the clinic.

Actin and actin polymerization factors regulate the immune system in a complex manner. The function in the cytoplasm has been well-established, where they are important components of the cytoskeleton, controlling cell migration, function, and vesicular transport. However, it remains poorly understood how they enter the nucleus to regulate immunological functions in B cells. Here, our study, through constructing a mouse model with specific WASH deletion in B cells, has shown that a deficiency of WASH leads to a decrease in BCR signaling and B cell metabolism, abnormal B cell differentiation, and a reduction of humoral response. Mechanistically, WASH interacts with pSTAT1 to promote the phosphorylation of STAT1, facilitating its translocation into the nucleus and regulating biological functions. Our study has unveiled the potential molecular mechanisms by which WASH influences B cell signaling, metabolism, and function through STAT1. These findings will offer potential avenues for therapeutic strategies targeting autoimmune diseases.

AIM2, an inflammasome sensor, has been extensively investigated for its ability to induce pyroptosis in macrophages. However, its role in the adaptive immune system remains poorly studied, particularly in B cells. AIM2 knockout mice had decreased follicular (FO) and marginal zone (MZ) B cell subsets and impaired IgG3 switching. The activation of B cells enhanced the co-localization of AIM2 and BCR. Interestingly, AIM2 exerts dual regulatory effects on BCR signaling transduction by positively regulating the PI3K-AKT signaling axis and negatively regulating the BTK-NFκB signaling axis. Through immunoprecipitation-mass spectrometry (IP-MS) analysis, SNX9 was identified as a critical molecule that promotes downstream signaling by facilitating the association of PI3K with CD19 in an AIM2-dependent manner. Furthermore, AIM2 is involved in the endocytosis of BCR and CD19 and the subsequent antigen uptake and presentation processes via SNX9-WASP interaction. In AIM2 knockout mice, this dual regulation leads to reduced overall BCR signaling characterized by decreased calcium signaling and reduced antibody production following RBD immunization. Conversely, AIM2 is overexpressed in B cells of Kawasaki disease patients, contributing to the development of this autoimmune disease. In summary, our study has unveiled a novel positive regulatory role of AIM2 in B cell receptor activation, endocytosis, and humoral response, focusing on AIM2-associated signaling pathways in B cells.