Cell Death and Differentiation最新文献

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.

The recent discovery of cell death mediated by metal ions has aroused significant interest in harnessing this novel mechanism of cell death for cancer therapy. As the two identified metal ion-based regulated cell death forms, ferroptosis and cuproptosis were initially studied separately, while increasing evidences underscored their intricate connections. Gastric cancer (GC) is one of the most severe malignant tumors of the digestive system. Targeting the complex interplay between ferroptosis and cuproptosis, and understanding their intrinsic mechanisms may offer approaches for developing innovative therapies in GC. Here, we identified that metal-regulatory transcription factor 1 (MTF1) was the key gene blocking the sensitivity of ferroptosis and cuproptosis enhanced by the combination treatment with FINO2 and ES-Cu in vitro and in vivo. Mechanistically, MTF1 suppressed FINO2/ES-Cu induced ferroptosis through upregulating FTH1 to reduce Fe²⁺ levels. In addition to direct transcriptional upregulation of FTH1, MTF1 activated TRIM31. Subsequently, TRIM31 catalyzed ubiquitination of NCOA4 and also promoted the expression of FTH1. On the other hand, it also activated iron-sulfur cluster assembly 2 (ISCA2)-mediated iron-sulfur cluster (ISC) assembly and iron starvation response to inhibit cuproptosis and ferroptosis. Collectively, our findings indicated the mechanism of the synergistic effect of ferroptosis and cuproptosis in the treatment of GC and presented a prospective therapeutic strategy through elucidating the molecular mechanism of ferroptosis and cuproptosis mediated by MTF1.

Tumor-derived exosome secretion dynamically correlates with malignant progression, although the mechanisms by which tumor-associated antigens regulate exosome production remain unclear. Here, we found that the number of plasma exosomes increased significantly with the progression of non-small-cell lung cancer (NSCLC) patients and identified that CD147 as a crucial mediator of exosome secretion using mass spectrometry. CD147 exhibited a positive correlation with exosomes release in NSCLC patients and various cell lines and it drove the release of exosome to promote tumor metastasis in vitro and in vivo. Transcriptomic profiling of transgenic CD147 models identified differential gene expression patterns enriched in autophagy-related pathways. Intriguingly, CD147 was found to specifically enhance autophagosome and amphisome biogenesis to promote exosomes release by using transmission electron microscopy, high-sensitivity structured light microscope, RFP-GFP-LC3 adenovirus reporters and immunofluorescence, which indicated the role of CD147 in mediating non-canonical autophagy processes. Mechanistically, CD147 activated the GCN2/EIF2α/ATG12 signaling axis to drive autophagosome assembly but blocked autolysosome maturation by inhibiting VAMP8/STX17/SNAP29-dependent fusion, leading to amphisome accumulation. Proteomics identified TRIM56 as a novel E3 ligase mediating K619 ubiquitination-dependent GCN2 proteasomal degradation. Subsequently, we found that CD147 suppresses TRIM56 expression, thereby stabilizing GCN2 to activate the GCN2/EIF2α/ATG12 axis. Meanwhile, CD147-induced IP3R3-mediated calcium overload facilitated the fusion of autophagosomes with multivesicular bodies to form amphisomes, thus enhancing exosome release. Collectively, our findings reveal a novel mechanism whereby CD147 promotes crinophagy-mediated exosome secretion through dual regulation of GCN2 stability and calcium homeostasis, thereby accelerating NSCLC progression. Our work establishes a new molecular link between autophagy modulation and cancer progression.

Pleural mesothelioma (PM) is an aggressive cancer that originates from mesothelial cells lining the pleura. To identify the different cell types in mesothelioma and their relationships, we performed single-cell RNAseq analyses of non-malignant pleura biopsies, PM biopsies and PM patient-derived organoids. Gene expression profiles of mesothelial and mesothelioma cells are very similar, suggesting that mesothelioma cells retain most properties of mesothelial cells. Surprisingly, in PM patient-derived organoids mesothelioma cells can acquire a fibroblast-like gene expression profile. Indeed, in most of the original PM biopsies a fraction of cells within the cluster of cancer-associated fibroblasts (CAFs) appear derived from tumor cells, with which they share the same genomic rearrangements. We confirmed by immunohistochemistry, and thus at the protein level, that cancer-derived fibroblast-like cells (CDFs) express smooth muscle actin, as most CAFs do, but have lost the same tumor suppressor proteins as the cognate mesothelioma cells. We propose that mesothelioma cells can become CDFs because they retain the ability of mesothelial cells to differentiate into fibroblasts. CDFs are thus tumor cells with fibroblast-like gene expression associated to tumors, and fulfil the definition of CAFs. CAFs generally support tumor progression, and in most tumors derive from resident fibroblasts or circulating mesenchymal cells. Our finding that a subset of CAFs derive from tumor cells, at least in mesothelioma, challenges current understanding of CAF origin. We suggest that interfering with the mesothelioma-to-CAF transition might offer an avenue to moderate tumor progression and resistance to therapy.

Metabolic reprogramming is a hallmark of clear-cell renal cell carcinoma (ccRCC), driving tumor progression and altering the tumor microenvironment (TME), making it crucial to understand metabolic dysregulation in ccRCC and to identify new therapeutic targets for patients. In this study, metabolomic profiling identified elevated levels of methylmalonic acid (MMA) in ccRCC, attributed to downregulation of methylmalonyl-CoA mutase (MMUT). MMA produced by ccRCC accumulates in the TME and activates the suppressor of fused (SUFU)-regulated Hedgehog signaling pathway in a dose-dependent manner, promoting M2 polarization of macrophages and tumor progression. Mechanistically, MMA induces methylmalonylation at the K499 site of ubiquitin-specific peptidase 36 (USP36), inhibiting USP36-mediated deubiquitination and SUMOylation of SUFU, thereby promoting the expression of GLI family zinc finger 1 (GLI1) and its target genes. Both in vitro and in vivo experiments demonstrated that a low branched-chain amino acids (BCAAs) diet or treatment with the de-methylmalonylation agent MC3138 effectively inhibited M2 polarization of macrophages and tumor progression. These findings emphasize the critical role of MMA in ccRCC pathogenesis and suggest that combining a low-BCAAs diet with MC3138 therapy may offer a promising treatment strategy for ccRCC patients with elevated MMA levels.

The mechanistic target of rapamycin complex 2 (mTORC2) signaling pathway, which regulates cell growth and migration, exhibits oncogenic function in colorectal cancer (CRC). mTORC2 signaling is primarily activated by a complex assembly of mTOR, RICTOR, SIN1, and mLST8; however, the mechanisms by which dysregulation of this pathway contributes to its oncogenic function remain elusive. Here, we show that the Src-Like Adaptor Protein (SLAP), a negative regulator of tyrosine kinase signaling receptors, controls mTORC2 integrity to mediate its tumor-suppressive function in CRC. Mechanistically, SLAP interacts with mLST8 and facilitates its non-degradative ubiquitination at lysines 86 and 215, thereby reducing the integrity of mTORC2 and mTORC2-AKT signaling. The E3 ubiquitin ligase UBE3C was identified as a novel SLAP interactor involved in this ubiquitination process. Functionally, SLAP inhibition of CRC cell growth and invasion was dependent upon mTORC2 signaling inhibition. In immunodeficient mice CRC xenografts, SLAP depletion enhanced mTORC2 activity and sensitized CRC cells to mTOR catalytic inhibitors. Together, our findings reveal a previously unrecognized SLAP-UBE3C-mLST8 axis that regulates mTORC2 integrity and suggest a potential therapeutic avenue for targeting mTORC2 in CRC.

Recent FDA approval for treating Alzheimer's disease (AD) with amyloid-beta (Aβ) immunotherapy is a historic breakthrough, which has rekindled widespread interest in understanding the molecular basis of Aβ toxicity. In this study, we developed a novel Drosophila model to investigate Aβ42-induced pathologies in vivo and in real time. Strikingly, we unveiled compelling evidence that secreted Aβ42 affects different neurons in distinct ways-both in susceptibility to Aβ42 deposition and in the mode of cell death triggered. Additionally, we observed altered larval crawling behaviour which-remarkably-could be recovered by inhibiting ferroptotic cell death with small molecule inhibitors. Collectively these findings showcase this as a powerful new model for investigating Aβ toxicity in AD and identifying novel treatment strategies.