Cell Death and Differentiation最新文献

Ferroptosis is one of the cell death programs occurring after spinal cord injury (SCI) and is driven by iron-dependent phospholipid peroxidation. However, little is known about its underlying regulation mechanism. The present study demonstrated that lipid peroxidation was promoted in patients with SCI. Neurons affected by ferroptosis following SCI had a high expression of ferroptotic protein ACSL4. The E3 SUMOylase TRIM28 promoted neuronal ferroptosis by enhancing ACSL4 expression. Genetic deletion of Trim28 significantly attenuated neuronal ferroptosis and improved mouse hindlimb motor function following SCI. In contrast, mice with Trim28 overexpression demonstrated poor neurological function after SCI, which was attenuated by ferroptosis inhibitor Liproxstatin-1. Mechanistically, TRIM28 bound to ACSL4, promoted SUMO3 modification at lysine (K) 532, and inhibited K63-linked ACSL4 ubiquitination, thereby suppressing OPTN-dependent autophagic degradation. Additionally, SENP3 was identified as the deSUMOylation enzyme that can reverse this process and compete with TRIM28, which was transcriptionally upregulated due to excessive oxidative stress. These data unveiled a mechanism by which TRIM28-mediated SUMOylation regulated neuronal ACSL4 levels and ferroptosis, identified interactions and correlations involved in ACSL4 SUMOylation, ubiquitination, and autophagic degradation, and discovered a positive feedback loop where oxidative stress transcriptionally upregulated Trim28, and conversely TRIM28 promoted ferroptosis and oxidative stress. Notably, screening of the FDA-approved drug library revealed that pharmacological TRIM28/ACSL4 axis interventions with Rutin hydrate inhibited neuronal ferroptosis and improved hindlimb motor function in mice after SCI, thus providing a promising therapeutic strategy for its treatment.

Aging is a major risk factor for Alzheimer’s disease (AD). With the prevalence of AD increased, a mechanistic linkage between aging and the pathogenesis of AD needs to be further addressed. Here, we report that a small ubiquitin-related modifier (SUMO) modification of p53 is implicated in the process which remarkably increased in AD patient’s brain. Mechanistically, SUMOylation of p53 at K386 residue causes the dissociation of SET/p53 complex, thus releasing SET into the cytoplasm, SET further interacts with cytoplasmic PP2A and inhibits its activity, resulting in tau hyperphosphorylation in neurons. In addition, SUMOylation of p53 promotes the p53 Ser15 phosphorylation that mediates neuronal senescence. Notably, p53 SUMOylation contributes to synaptic damage and cognitive defects in AD model mice. We also demonstrate that the SUMOylation inhibiter, Ginkgolic acid, recovering several senescent phenotypes drove by p53 SUMOylation in primary neurons. These findings suggest a previously undiscovered etiopathogenic relationship between aging and AD that is linked to p53 SUMOylation and the potential of SUMOylated p53-based therapeutics for neurodegeneration such as Alzheimer’s disease.

Hyperactivation of the YAP/TEAD transcriptional complex in cancers facilitates the development of an immunosuppressive tumor microenvironment. Herein, we observed that the transcription factor SP1 physically interacts with and stabilizes the YAP/TEAD complex at regulatory genomic loci in colorectal cancer (CRC). In response to serum stimulation, PKCζ (protein kinase C ζ) was found to phosphorylate SP1 and enhance its interaction with TEAD4. As a result, SP1 enhanced the transcriptional activity of YAP/TEAD and coregulated the expression of a group of YAP/TEAD target genes. The immune checkpoint V-domain Ig suppressor of T-cell activation (VISTA) was identified as a direct target of the SP1-YAP/TEAD4 complex and found to be widely expressed in CRC cells. Importantly, YAP-induced VISTA upregulation in human CRC cells was found to strongly suppress the antitumor function of CD8⁺ T cells. Consistently, elevated VISTA expression was found to be correlated with hyperactivation of the SP1-YAP/TEAD axis and associated with poor prognosis of CRC patients. In addition, we found by serendipity that enzymatic deglycosylation significantly improved the anti-VISTA antibody signal intensity, resulting in more accurate detection of VISTA in clinical tumor samples. Overall, our study identified SP1 as a positive modulator of YAP/TEAD for the transcriptional regulation of VISTA and developed a protein deglycosylation strategy to better detect VISTA expression in clinical samples. These findings revealed a new tumor cell-intrinsic mechanism of YAP/TAZ-mediated cancer immune evasion.

Cancer stem cells (CSCs) typically reside in perivascular niches, but whether endothelial cells of blood vessels influence the stemness of cancer cells remains poorly understood. This study revealed that endothelial cell-specific GLTSCR1 deletion promotes colorectal cancer (CRC) tumorigenesis and metastasis by increasing cancer cell stemness. Mechanistically, knocking down GLTSCR1 induces the transformation of endothelial cells into tip cells by regulating the expression of Neuropilin-1 (NRP1), thereby increasing the direct contact and interaction between endothelial cells and tumour cells. In addition, GLTSCR1 inhibits JAG1 transcription by competing with acetylated p65^(Lys-310) to bind to the BRD4 interaction site. Therefore, GLTSCR1 deficiency increases JAG1 expression in endothelial cells. Subsequently, increased JAG1 levels on tip cell membranes bind to Notch on CRC cell membranes, activating the Notch signalling pathway in tumour cells and increasing CRC cell stemness. Taken together, our findings highlight the roles of endothelial cells in CRC development.

Immunity suffers a function deficit during aging, and the incidence of cancer is increased in the elderly. However, most cancer models employ young mice, which are poorly representative of adult cancer patients. We have previously reported that Triple-Therapy (TT), involving antigen-presenting-cell activation by vinorelbine and generation of TCF1⁺-stem-cell-like T cells (scTs) by cyclophosphamide significantly improved anti-PD-1 efficacy in anti-PD1-resistant models like Triple-Negative Breast Cancer (TNBC) and Non-Hodgkin’s Lymphoma (NHL), due to T-cell-mediated tumor killing. Here, we describe the effect of TT on TNBC growth and on tumor-microenvironment (TME) of young (6–8w, representative of human puberty) versus adult (12 m, representative of 40y-humans) mice. TT-efficacy was similar in young and adults, as CD8⁺ scTs were only marginally reduced in adults. However, single-cell analyses revealed major differences in the TME: adults had fewer CD4⁺ scTs, B-naïve and NK-cells, and more memory-B-cells. Cancer-associated-fibroblasts (CAF) with an Extracellular Matrix (ECM) deposition-signature (Matrix-CAFs) were more common in young mice, while pro-inflammatory stromal populations and myofibroblasts were more represented in adults. Matrix-CAFs in adult mice displayed decreased ECM-remodeling abilities, reduced collagen deposition, and a different pattern of interactions with the other cells of the TME. Taken together, our results suggest that age-dependent differences in the TME should be considered when designing preclinical studies.

The cell death receptor FAS and its ligand (FASLG) play crucial roles in the selection of B cells during the germinal center (GC) reaction. Failure to eliminate potentially harmful B cells via FAS can lead to lymphoproliferation and the development of B cell malignancies. The classic form of follicular lymphoma (FL) is a prototypic GC-derived B cell malignancy, characterized by the t(14;18)(q32;q21)IGH::BCL2 translocation and overexpression of antiapoptotic BCL2. Additional alterations were shown to be clinically relevant, including mutations in ARID1A. ARID1A is part of the SWI/SNF nucleosome remodeling complex that regulates DNA accessibility (“openness”). However, the mechanism how ARID1A mutations contribute to FL pathogenesis remains unclear. We analyzed 151 FL biopsies of patients with advanced-stage disease at initial diagnosis and found that ARID1A mutations were recurrent and mainly disruptive, with an overall frequency of 18%. Additionally, we observed that ARID1A mutant FL showed significantly lower FAS protein expression in the FL tumor cell population. Functional experiments in BCL2-translocated lymphoma cells demonstrated that ARID1A is directly involved in the regulation of FAS, and ARID1A loss leads to decreased FAS protein and gene expression. However, ARID1A loss did not affect FAS promotor openness. Instead, we identified and experimentally validated a previously unknown co-transcriptional complex consisting of RUNX3 and ETS1 that regulates FAS expression, and ARID1A loss leads to reduced RUNX3 promotor openness and gene expression. The reduced FAS levels induced by ARID1A loss rendered lymphoma cells resistant to both soluble and T cell membrane-anchored FASLG-induced apoptosis, and significantly diminished CAR T cell killing in functional experiments. In summary, we have identified a functionally and clinically relevant mechanism how FL cells can escape FAS-dependent immune surveillance, which may also impact the efficacy of T cell-based therapies, including CAR T cells.

Accumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the Homeobox A2 (HOXA2) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of HOXA2 in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of HOXA2 was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of HOXA2 and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of HOXA2 in human BC tissues. Low HOXA2 expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of HOXA2 expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic HOXA2 overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored HOXA2 expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of HOXA2 leaded to a concomitantly decreased expression of PPARγ and its target CIDEC, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies HOXA2 as a novel prognosis-relevant tumor suppressor in the mammary gland.

Recent studies have implicated altered ubiquitination/de-ubiquitination pathway in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the potential role of a deubiquitinase, ubiquitin-specific peptidase 25 (USP25), in MASLD. Analysis of mRNA profiling data showed that both human and mouse MASLD are associated with reduced expression of USP25 in hepatocytes. Usp25 deficiency exacerbated HFD-induced liver lipid accumulation and MASLD in mice. Rescue experiments with USP25 induction in hepatocytes protected mice against HFD-induced MASLD. Through comprehensive transcriptome sequence and pulldown-LC-MS/MS analysis, we identified that peroxisome proliferator-activated receptor α (PPARα) is involved in USP25’s protective actions and may be the substrate protein of USP25. Cell-based experiments show that USP25 interacts with PPARα directly via its USP domain and the histidine at position 608 of USP25 exerts deubiquitination to increase protein stability by removing the K48 ubiquitin chain at PPARα’s lysine at position 429. USP25 reduces palmitate (PA)-induced lipid accumulation in hepatocytes via increasing PPARα. Finally, we show that the protective effects of Usp25 induction are nullified in Ppara-deficient mice with HFD. In summary, this study presents a new USP25-PPARα axis in hepatocytes and highlights a novel function of USP25 in MASLD, suggesting that it may be targeted to combat the disease.

Clinical treatment options for triple-negative breast cancer (TNBC) are currently limited to chemotherapy because of a lack of effective therapeutic targets. Recent evidence suggests that long noncoding RNAs (lncRNAs) encode bioactive peptides or proteins, thereby playing noncanonical yet significant roles in regulating cellular processes. However, the potential of lncRNA-translated products in cancer progression remains largely unknown. In this study, we identified a previously undocumented small protein encoded by the lncRNA LINC02870. This protein is localized at the endoplasmic reticulum (ER) and participates in ER stress, thus, we named it the endoplasmic reticulum stress protein (ERSP). ERSP was highly expressed in TNBC tissues, and elevated LINC02870 content was correlated with poor prognosis in TNBC patients. Loss of ERSP inhibited TNBC growth and metastasis both in vitro and in vivo. The pro-oncogenic effects of ERSP could be attributed to its selective activation of the IRE1α/XBP1s branch. ERSP enhances the unfolded protein response (UPR) by interacting with XBP1s, facilitating the nuclear accumulation of XBP1s, thereby promoting the expression of ER stress-related genes. These findings highlight the regulatory role of the lncRNA-encoded protein ERSP in ER stress and suggest that it is a potential therapeutic target for TNBC.

Fungi are the most important group of plant pathogens, responsible for many of the world’s most devastating crop diseases. One of the reasons they are such successful pathogens is because several fungi have evolved the capacity to breach the tough outer cuticle of plants using specialized infection structures called appressoria. This is exemplified by the filamentous ascomycete fungus Magnaporthe oryzae, causal agent of rice blast, one of the most serious diseases affecting rice cultivation globally. M. oryzae develops a pressurized dome-shaped appressorium that uses mechanical force to rupture the rice leaf cuticle. Appressoria form in response to the hydrophobic leaf surface, which requires the Pmk1 MAP kinase signalling pathway, coupled to a series of cell-cycle checkpoints that are necessary for regulated cell death of the fungal conidium and development of a functionally competent appressorium. Conidial cell death requires autophagy, which occurs within each cell of the spore, and is regulated by components of the cargo-independent autophagy pathway. This results in trafficking of the contents of all three cells to the incipient appressorium, which develops enormous turgor of up to 8.0 MPa, due to glycerol accumulation, and differentiates a thickened, melanin-lined cell wall. The appressorium then re-polarizes, re-orienting the actin and microtubule cytoskeleton to enable development of a penetration peg in a perpendicular orientation, that ruptures the leaf surface using mechanical force. Re-polarization requires septin GTPases which form a ring structure at the base of the appressorium, which delineates the point of plant infection, and acts as a scaffold for actin re-localization, enhances cortical rigidity, and forms a lateral diffusion barrier to focus polarity determinants that regulate penetration peg formation. Here we review the mechanism of regulated cell death in M. oryzae, which requires autophagy but may also involve ferroptosis. We critically evaluate the role of regulated cell death in appressorium morphogenesis and examine how it is initiated and regulated, both temporally and spatially, during plant infection. We then use this synopsis to present a testable model for control of regulated cell death during appressorium-dependent plant infection by the blast fungus.