Cell Death and Differentiation最新文献

Excessive neutrophil activation and neutrophil extracellular trap (NET) release drive systemic inflammation and organ injury in sepsis, yet the upstream regulatory pathways remain incompletely defined. Here, we identify epidermal growth factor receptor (EGFR) as a critical neutrophil-intrinsic regulator of NETosis. EGFR expression was markedly elevated in neutrophils from patients with sepsis and correlated with disease severity. Neutrophil-specific EGFR deletion in mice improved survival after polymicrobial sepsis by reducing cytokine storm, tissue injury, and NET formation. Mechanistically, EGFR associated with CCAAT/enhancer-binding protein beta (CEBPβ) and recruited Mitogen-activated protein kinase 14 (MAPK14) to phosphorylate CEBPβ, promoting its nuclear localization and transcriptional activation of peptidoglycan recognition protein 1 (PGLYRP1). Elevated PGLYRP1, in turn, amplified NETs release via autocrine engagement of triggering receptor expressed on myeloid cell-1 (TREM-1), establishing a feed-forward inflammatory loop. Administration of recombinant PGLYRP1 or forced CEBPβ overexpression reversed the protection conferred by EGFR deficiency, confirming the centrality of this axis. These findings define an unrecognized EGFR-MAPK14-CEBPβ-PGLYRP1-TREM1 circuit that links receptor signaling to pathological NETosis and highlight a promising therapeutic target to attenuate neutrophil-driven immunopathology in sepsis.

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.