Cell Death and Differentiation最新文献

Focal inflammation and arterial damage driven by macrophages are key pathogenic processes in atherosclerosis. However, the mechanisms that regulate these processes remain poorly understood. In this study, we demonstrate that formyl peptide receptor 1 (FPR1) agonist, a mitochondrial N-formyl peptide, is elevated in the blood of patients with atherosclerosis and correlates with carotid stenosis. Macrophages expressing FPR1 were found in atherosclerotic lesions. Conditional deletion of Fpr1 in macrophages reduced plaque formation, local inflammation, and aortic atherosclerosis in apolipoprotein E (ApoE)^−/− mice. FPR1 activates protein kinase C (PKC) in macrophages, promoting the production of reactive oxygen species (ROS), tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β), which accelerates the apoptosis of endothelial cells and smooth muscle cells. To inhibit FPR1 bioactivity, we developed an antagonist, T0080. Therapeutic administration of T0080 attenuates atherosclerotic progression in ApoE^−/− mice. Our findings highlight the pivotal role of FPR1 in macrophage-mediated atherosclerotic plaque formation and support further investigation of T0080-mediated FPR1 inhibition as a potential treatment for atherosclerosis.

Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients, is characterized by its aggressive nature and poor prognosis. In this study, we identify decapping mRNA 1B (DCP1B) as a tumor suppressor gene that is transcriptionally regulated by p53. DCP1B is found to inhibit the growth and migration of NSCLC cells. Consistently, the level of DCP1B expression is decreased in NSCLC tissues, and its low expression is associated with NSCLC patients’ unfavorable outcomes. Mechanistic investigations reveal that DCP1B promotes the turnover of mitogen-activated protein kinase 4 (MAPK4) mRNA, and the activation of p53 reduces the expression level of MAPK4 partially through DCP1B. Notably, overexpression of MAPK4 can drive AKT phosphorylation independent of phosphoinositide 3-kinase (PI3K), thus neutralizing the anti-tumor activity of the PI3K inhibitor in NSCLC cells. Moreover, the p53 agonist combined with the PI3K inhibitor can suppress NSCLC proliferation synergistically in vitro and in vivo. Collectively, this study not only uncovers the function and mechanism of the p53-DCP1B-MAPK4 axis in suppressing NSCLC progression but also suggests a promising combination strategy for treating NSCLC.

Accumulating evidence indicates that metabolic enzymes can directly couple metabolic signals to transcriptional adaptation and cell differentiation. Glycogen synthase 1 (GYS1), the key metabolic enzyme for glycogenesis, is a nucleocytoplasmic shuttling protein compartmentalized in the cytosol and nucleus. However, the spatiotemporal regulation and biological function of nuclear GYS1 (nGYS1) microcompartments remain unclear. Here, we show that GYS1 dynamically reorganizes into nuclear condensates under conditions of glycogen depletion or transcription inhibition. nGYS1 complexes with the transcription factor NONO/p54^nrb and undergoes liquid–liquid phase separation to form biomolecular condensates, leading to its nuclear retention and inhibition of glycogen biosynthesis. Compared to their wild-type littermates, Nono-deficient mice exhibit exercise intolerance, higher muscle glycogen content, and smaller myofibers. Additionally, Gys1 or Nono deficiency prevents C2C12 differentiation and cardiotoxin-induced muscle regeneration in mice. Mechanistically, nGYS1 and NONO co-condense with the myogenic transcription factor MyoD and preinitiation complex (PIC) proteins to form transcriptional condensates, driving myogenic gene expression during myoblast differentiation. These results reveal the spatiotemporal regulation and subcellular function of nuclear GYS1 condensates in glycogenesis and myogenesis, providing mechanistic insights into glycogenoses and muscular dystrophy.

Hepatic very low-density lipoprotein (VLDL) is essential for maintaining lipid metabolism in the liver. Sphingosine kinases (SphKs) are essential rate-limiting enzymes that catalyze sphingosine phosphorylation to Sphingosine-1-phosphate (S1P). SphKs exist as two isoforms, SphK1 and SphK2, both highly expressed in the liver. SphK1 plays a critical role in regulating hepatic inflammation and drug metabolism. This study aimed to determine whether SphK2 regulates hepatic lipid metabolism, particularly VLDL secretion. Immunohistochemical staining revealed decreased SphK2 protein levels within regions proximal to hepatic lipid accumulation in individuals diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD). Sphk2^−/− mice exhibited spontaneous hepatocyte lipid accumulation and reduced VLDL secretion. Proteomic analysis revealed that SphK2 deficiency impaired soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) complex interactions involved in vesicular transport and organelle membrane fusion. Furthermore, SphK2 deficiency results in accelerated degradation of the SEC22B, STX5A, and GS28 proteins via chaperone-mediated autophagy (CMA), impeding VLDL transport to the Golgi apparatus. MYH1485, a specific activator of mTOR, induces mTORC2 phosphorylation, thereby inhibiting the degradation of SNARE complexes by CMA and counteracting the lipid accumulation induced by SphK2 deficiency. Exogenous S1P supplementation markedly reversed the reduction in mTORC2 phosphorylation and suppressed CMA, thereby improving VLDL secretion. Our study elucidates an inventive regulatory mechanism by which SphK2 modulates CMA by activating mTORC2 phosphorylation, promoting VLDL secretion, and balancing lipid metabolism in the liver. These findings provide insights into SphK2 function and the underlying mechanisms involved in the regulation of VLDL secretion, which may facilitate MASLD treatment.

Mutations in the tumor suppressor gene Folliculin (FLCN) are responsible for Birt-Hogg-Dube’ (BHD) syndrome, a rare inherited condition that predisposes affected individuals to skin tumors, pulmonary cysts, and kidney tumors. FLCN regulates key cellular pathways, including TFEB, TFE3, and mTORC1, which are critical for maintaining cell homeostasis. Loss of FLCN leads to both hyperactivation of mTORC1 and constitutive activation of TFEB and TFE3, contributing to tumorigenesis. While previous studies showed that Flcn liver-specific conditional knockout (Flcn^LiKO) mice are protected from developing liver fibrosis and damage upon high-fat diet exposure, the potential role of FLCN loss in liver carcinogenesis remained unexplored. Here, we demonstrate that hepatic loss of FLCN in mice results in cancer associated with inflammation and fibrosis with features of cholangiocarcinoma (CCA). This phenotype emerges in mice over 90-week-old, with a male predominance. Moreover, Flcn^LiKO mice are more prone to develop diethylnitrosamine (DEN)- or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- induced liver tumors with heterogenous histological features. Notably, depletion of TFE3, but not TFEB, in the liver of Flcn^LiKO mice fully rescues the cancer phenotype and normalized mTORC1 signaling, highlighting TFE3 as the primary driver of liver cancer and mTORC1 hyperactivity in the absence of FLCN.

Tumor cells evolve strong antioxidant capacities to counteract the abnormal high level of reactive oxygen species (ROS) in the tumor microenvironment. Glutamate-cysteine ligase catalyzing subunit (GCLC) for synthesis of antioxidant glutathione (GSH) represents the key enzyme to maintain redox homeostasis of tumor cells, however, whether its activity is regulated by posttranslational modifications, such as succinylation, remains to be clarified. Here, we demonstrate the existence of succinylation modification on GCLC by in vitro and in vivo assays. NAD-dependent deacetylase Sirtuin-2 (SIRT2) serves as the desuccinylase and catalyzes GCLC desuccinylation at sites of K38, K126, and K326. Specifically, GCLC directly interacts with SIRT2, which can be substantially enhanced upon ROS treatment. This strengthened association results in GCLC desuccinylation and activation, consequently promoting GSH synthesis and rendering cancer cells resistant to ferroptosis induction. Depletion of SIRT2 decreases total GSH level and meanwhile increases the cellular susceptibility to ferroptosis, which can mostly be rescued by introducing wild-type GCLC, but not its 3K-E mutant. We further demonstrated that histone acetyltransferase P300 serves as the succinyltransferase of GCLC, and their association is remarkably decreased after ROS treatment. Thus, SIRT2-regulated GCLC succinylation represents an essential signaling axis for cancer cells to maintain their redox balance in coping with oxidative stress-induced ferroptosis.

Glioblastoma (GBM) is the most primary lethal brain cancer, characterized by the presence of glioblastoma stem cells (GSCs) that initiate and sustain tumor growth and induce radioresistance. Annexin A2 (ANXA2) has been reported to contribute to glioblastoma progression and impart stem cell-like properties to GSCs, however, its post-translational modifications and mechanisms in GSCs maintenance remain poorly understood. Here, we identify that USP4 is preferentially expressed by GSCs in GBM, USP4/ANXA2 supports GSCs maintenance and radioresistance. Specifically, USP4 interacts with ANXA2, stabilizing its protein by deubiquitinating ANXA2, which mediates its proteasomal degradation and Y24 phosphorylation. USP4 directly cleaves Lys48- and Lys63-linked polyubiquitin chains of ANXA2, with the Lys63-linked polyubiquitin chains of ANXA2 K28 mediating its Y24 phosphorylation. Moreover, K10 acetylation of ANXA2 enhances its interaction with USP4. Importantly, USP4/ANXA2 promotes GSCs maintenance and radioresistance by activating BMX-mediated STAT3 activation. H3K18 lactylation is responsible for the upregulation of USP4 in GSCs. Our studies reveal that USP4/ANXA2 plays critical roles in maintaining GSCs and therapeutic resistance, highlighting the importance of lactylation, acetylation, ubiquitination, and phosphorylation as critical post-translational modifications for USP4-mediated stabilization and activity of ANXA2.

Selective autophagy is a finely regulated degradation pathway that can either promote or suppress cancer progression depending on its specific target cargoes. In this study, we report that transmembrane 9 superfamily member 1 (TM9SF1) suppresses colorectal cancer metastasis via selective autophagic degradation of Vimentin. Tm9sf1 knockout significantly increases tumor numbers and size, as well as enhances tumor invasion in colorectal cancer model. In vitro and in vivo phenotypical analyses reveal that TM9SF1 functions as a metastasis suppressor in colorectal cancer. Mechanistically, TM9SF1 facilitates the K63-linked ubiquitination of Vimentin by the E3 ligase TRIM21. The K63-linked ubiquitination of Vimentin serves as a recognition signal for autophagic degradation mediated by autophagic cargo receptor Tollip. Consequently, the downregulation of Vimentin results in a decreased number of F-actin-rich stress fibers and filopodium-like protrusions, ultimately inhibiting colorectal cancer metastasis. Moreover, TM9SF1 is downregulated in colorectal cancer patients with advanced stage compared to those with early stage and associated with favorable prognosis. Overall, our findings identify a novel TM9SF1-TRIM21-Vimentin-Tollip pathway involved in colorectal cancer metastasis, which may provide promising therapeutic targets for the treatment of metastatic colorectal cancer.

DEPTOR, a naturally occurring inhibitor of mTOR, plays crucial roles in tumorigenesis and is frequently dysregulated in a variety of human cancers. Interestingly, DEPTOR could act either as a tumor suppressor or as an oncogene in a manner dependent of cellular context or tissue environment. Whether and how DEPTOR regulates lymphomagenesis remains elusive. In this study, we report that in a mouse lymphoma model induced by heterozygous Pten loss, Deptor knockout (KO) markedly accelerates lymphomagenesis, whereas degradation-resistant Deptor^S275A knock-in (KI) variant significantly inhibits it. Furthermore, Deptor KO mice spontaneously developed lymphomas in the later stages of their lifespan, and Deptor KO further shortened overall lifespan in Pten^fl/fl;MMTV-Cre mice. Consistently, DEPTOR protein levels are significantly lower in human lymphoma tissues, as compared to normal lymph nodes. Mechanistically, DEPTOR, on one hand, enhances the interaction of EGFR to HUWE1 E3 ubiquitin ligase for targeted ubiquitination and proteasomal degradation, and subsequent inactivation of the MAPK signal. On the other hand, DEPTOR inactivates both mTORC1 and mTORC2 signals. Collectively, our study demonstrated that DEPTOR is a tumor suppressor that inhibits lymphomagenesis upon Pten-loss. The strategy that reactivates DEPTOR could be a promising approach for the treatment of lymphoma.

Cell death is a natural part of the development of multicellular organisms and is central to their physiological and pathological states. However, the existence of regulated cell death in unicellular microorganisms, including eukaryotic and prokaryotic microbes, has been a topic of debate. One reason for the continued debate is the lack of obvious benefit from cell death in the context of a single cell. However, unicellularity is relative, as most of these microbes dwell in communities of varying complexities, often with complicated spatial organization. In these spatially organized microbial communities, such as yeast and bacterial colonies and biofilms growing on solid surfaces, cells differentiate into specialized types, and the whole community often behaves like a simple multicellular organism. As these communities develop and age, cell death appears to offer benefits to the community as a whole. This review explores the potential roles of cell death in spatially organized communities of yeasts and draws analogies to similar communities of bacteria. The natural dying processes in microbial cell communities are only partially understood and may result from suicidal death genes, (self-)sabotage (without death effectors), or from non-autonomous mechanisms driven by interactions with other differentiated cells. We focus on processes occurring during the stratification of yeast colonies, the formation of the extracellular matrix in biofilms, and discuss potential roles of cell death in shaping the organization, differentiation, and overall physiology of these microbial structures.