Cell Death & Disease最新文献

Immunotherapy has emerged as a promising approach in the management of cancer. However, the suboptimal efficacy of immunotherapy monotherapy underscores the need to develop more effective combination strategies. In this study, we focused on PSMD1 to investigate its role and the molecular pathways by which it regulates the response to immunotherapy in hepatocellular carcinoma (HCC). In HCC, elevated PSMD1 levels are linked to associated with poor prognosis. PSMD1 was predominantly expressed in malignant epithelial cells. Tissue microarray results showed that PSMD1 was highly expressed in tumor tissues. Silencing PSMD1 suppressed HCC cell proliferation and promoted apoptosis in both in vitro and in vivo models. Additionally, PSMD1 suppression decreased PD-L1 expression, thereby enhancing the therapeutic efficacy of anti-PD-1 therapy. Mechanistically, publicly available single-cell RNA sequencing (scRNA-seq) datasets indicated that PSMD1 positively regulates β-catenin signaling. Silencing of PSMD1 decreased the expression of β-catenin pathway-associated proteins. Further analysis via mass spectrometry revealed that PSMD1 interacts with Rhotekin (RTKN) and suppresses its ubiquitination. Subsequent experiments revealed that RTKN enhances β-catenin expression through AKT phosphorylation, thereby increasing PD-L1 transcription. In summary, our findings demonstrate that PSMD1 regulates RTKN protein expression, whereas RTKN facilitates β-catenin expression via AKT phosphorylation. This mechanism contributes to HCC progression and the effectiveness of immunotherapy. The PSMD1/RTKN/β-catenin axis could serve as a promising therapeutic target for HCC.

Neutrophils, the first cells to arrive at the site of inflammation, are rather short-lived cells and thus have to be constantly replenished. During neutrophil development, vesicle dynamics need to be fine-tuned and impaired vesicle trafficking has been linked to failure in neutrophil maturation. Here, we characterized the role of VPS18 as a central core component of CORVET & HOPS tethering complexes for neutrophil development. Using CRISPR/Cas9-engineered Hoxb8 cells with heterozygous mutations in Vps18, we found that VPS18 deficiency interfered with neutrophil development due to tethering complex instability. As a result, vesicle dynamics were impaired with a strong increase in LC3B-II and p62 levels, indicating autophagosome accumulation and reduced autophagic flux. With transmission electron microscopy, we verified the increase in autophagosomes and also found irregularly shaped vesicular structures in Vps18 mutants. Subsequently, Vps18 mutant neutrophil progenitors underwent premature apoptosis. We described a novel patient with a heterozygous stop-gain mutation in VPS18 suffering from neutropenia and recurrent infections. To verify our findings in the human system, we used human induced pluripotent stem cells (iPSCs). Upon differentiation into neutrophils, loss of VPS18 resulted in an almost complete absence of iPSC-derived developing neutrophils. Heterozygous VPS18 mutant and patient mutation-harboring iPSCs were characterized by strongly reduced numbers of developing neutrophils. Zebrafish larvae with heterozygous mutations in vps18 were also characterized by significantly reduced neutrophil numbers. This study shows the pivotal impact of VPS18 for adequate vesicle dynamics during neutrophil development which might be relevant in the context of vesicle trafficking during granulopoiesis and congenital neutropenia.

Lipophagy is a form of selective autophagy that targets the lipid droplets for lysosomal decay and has been implicated in the onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Factors that augment lipophagy have been identified as targets for MASLD therapeutic development. TMEM55B is a key regulator of lysosomal positioning, which is critical for lysosome fusion with the autophagosome, but is less well studied. Here, we demonstrate that the absence of TMEM55B in murine models accelerates MASLD onset and progression to metabolic dysfunction-associated steatohepatitis (MASH). In cellular models, TMEM55B deficiency enhances incomplete lipophagy, whereby lysosome-lipid droplet interactions are increased, but lysosomal cargo is not fully degraded and/or released, leading to the development of lipid-filled lysosomes (lipolysosomes). Loss of TMEM55B also impairs mitophagy, causing an accumulation of dysfunctional mitochondria. This imbalance leads to increased lipid accumulation and oxidative stress, worsening MASLD. These findings underscore the importance of lysosomal positioning in lipid metabolism and suggest that targeting lipophagy for MASLD therapeutic development should be carefully considered to ensure promotion of the entire lipophagic flux pathway and whether it occurs in the context of mitochondrial dysfunction.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution. Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms. The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes. Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID. The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue. Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence. The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.

Integration of high-risk human papillomavirus into specific loci of the genome is a pivotal event in cervical carcinogenesis; however, it's underlying mechanism remains largely undefined. Here, through establishing an 8q24 site-specific HPV18 gene knock-in cell model by utilizing the CRISPR/Cas9 system, we discover that HPV18 knock-in (HPV-KI) results in a global alteration of the genome's topologically associating domain structure and an up-regulation of cancer-related genes in HPV^- HaCaT cells, among which the significantly up-regulated IL-17 signaling pathway and S100A8/A9 are partitularly prominent. Further mechanistic study demonstrate that HPV-KI reprograms metabolic pathway, especially up-regulates glycolysis and subsequently facilitates glycerolipid synthesis in HaCaT cell, leading to sphingosine-1-phospate (S1P) secretion and enhanced SpHK1/S1P/S1PR1 signaling pathway, thereby activating the the MAPK and NF-κB signaling pathways followed by inducing the expression of S100A8/A9, and hence induces the malignant transformation of cells. Importantly, inhibition of the S1P/S1PR1 signaling pathway down-regulates the expression of S100A8/A9 and suppresses the growth of HPV-KI cells and xenograft derived from cervical cancer patient. These findings provide novel insights into HPV integration-induced cervical carcinogenesis and identify potential therapeutic targets for its treatment.

The impaired repair of intestinal mucosal damage is an important pathological feature of ulcerative colitis (UC). The critical role of intestinal epithelial cells (IECs) proliferation and migration in the repair of damaged mucosal epithelium has been well established. However, the molecular circuitry that decodes IECs sense intestinal mucosal damage signals to initiate and drive repair program remains elusive. Here, we identify a tryptophan (Trp) metabolic gatekeeping mechanism wherein G protein-coupled receptor 35 (GPR35) senses intestinal mucosal damage through monitoring Trp-kynurenine (KYN)-kynurenic acid (KA) axis metabolism with a unique "sandwich" structural binding mode. We delineate a GPR35-Kruppel-like factor 5 (KLF5) regulatory circuit in which KLF5 serves as the central effector, translating GPR35-mediated KA sensing into repair programming through PI3K-AKT-mTOR signaling cascade. This circuitry precisely orchestrates IECs proliferation and migration by regulating KLF5-dependent gene expression networks that essential for restoring damaged mucosa. Once this metabolic gatekeeping system is disrupted, either through impaired GPR35-mediated KA sensing or defective signal transduction, compromises damage signal decoding, leading to inadequate repair responses. Such dysregulation results in delayed intestinal mucosal repair and exacerbation of tissue damage. Our findings highlight GPR35 as a surveillant of abnormal Trp-KYN-KA axis metabolism, enabling IECs to detect intestinal mucosal damage and orchestrate repair through KLF5 response. This provides important implications for UC prevention and treatment by targeting GPR35-KLF5 circuit.