Figure - available from: Nature Communications
This content is subject to copyright. Terms and conditions apply.
Zfp335cKO DN4 thymocytes undergo increased rates of apoptosis a, b Assessment of developmental progression throughout OP9-DL1 culture seeded with WT (black) or Zfp335cKO (red) DN3a thymocytes. Proliferation assessment (c, d by Cell Trace Violet (CTV) dilution and apoptosis analysis (e, f) based on Annexin V binding at day 3, 5, or 7 of culture. g Representative comparison of CTV dilution between Annexin V⁺ and viable (DAPI⁻ Annexin V⁻) cells on day 5 of culture. h Representative CD4 vs CD8 expression among Annexin V⁺ cells on day 5 of culture. n = 6 WT or n = 5 Zfp335cKO male and female mice from three independent experiments. P-values determined using two-way repeated-measures ANOVA with post hoc Sidak’s test. Plots show mean ± SEM. Source data are provided as a Source Data file.
Source publication
Production of a functional peripheral T cell compartment typically involves massive expansion of the bone marrow progenitors that seed the thymus. There are two main phases of expansion during T cell development, following T lineage commitment of double-negative (DN) 2 cells and after successful rearrangement and selection for functional TCRβ chain...
Similar publications
The αβ and γδ T cell lineages both differentiate in the thymus from common uncommitted progenitors. The earliest stage of T cell development is known as CD4⁻CD8⁻ double negative 1 (DN1), which has previously been shown to be a heterogenous mixture of cells. Of these, only the CD117⁺ fraction has been proposed to be true T cell progenitors that prog...
Citations
... Apoptosis greatly exacerbates the progression of neurodegenerative disorders including EP [33] and that cGAS/ STING triggers apoptosis of DN4 cells [34]. To explore the role of cGAS/STING pathway in EP, we examined the cGAS, STING and p-IRF3 protein levels in mice brain tissue samples. ...
The beneficial effects of gut flora on reducing nerve cell apoptosis and inflammation and improving epilepsy (EP) symptoms have been reported, but the specific mechanism of action is still unclear. A series of in vitro and in vivo experiments revealed the relationship between gut microbiota metabolites and the cGAS/STING axis and their role in EP. These results suggest that antibiotic-induced dysbiosis of gut microbiota exacerbated epileptic symptoms, probiotic supplements reduced epileptic symptoms in mice. Antibiotics and probiotics altered the diversity and composition of gut microbiota. The changes in gut bacteria composition, such as in the abundance of Firmicutes, Bacteroidetes, Lactobacillus and Ruminococcus, were associated with the production of short-chain fatty acids (SCFA) in the gut. The concentrations of propionate, butyrate and isovalerate were changed after feeding antibiotics and probiotics, and the increase in butyrate levels reduced the expression of cGAS/STING in nerve cell further reduced Bax protein expression. The reduction of Bax protein attenuated the hippocampal neuron cell apoptosis in PTZ-induced EP and EP progression. Our findings provide new insights into the roles and mechanisms of action of the gut microbiota in attenuating EP symptoms and progression.
Graphical Abstract
... It can activate transcription by recruiting histone methyltransferase complexes to the promoters of genes [32]. ZNF335 is widely expressed across human tissues [37] and has diverse functions, including roles in neuronal development [32] and T-cell maturation [23,38,39]. Here, we demonstrate for the first time that ZNF335 influences plasma cholesterol levels and statin response. ...
Background
Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained.
Methods
To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 μM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial ( ClinicalTrials.gov Identifier: NCT00451828 ). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified ( ZNF335 ), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335 ).
Results
The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR=5%). The two genes with the strongest correlations were zinc finger protein 335 ( ZNF335 aka NIF-1 , rho=0.237, FDR-adj p=0.0085) and CCR4-NOT transcription complex subunit 3 ( CNOT3 , rho=0.233, FDR-adj p=0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild type C57BL/6J mice in a sex combined model (p=0.04). Furthermore, male (but not female) mice carrying the Zfp335 R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (−43±18% and -23±19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335 R1092W allele(s) exhibited a significantly blunted LDL statin response.
Conclusions
Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.
... It has been shown that dsDNA could be recognized by cyclic GMP-AMP synthase (cGAS), leading to innate immune response and/or cell death [76]. cGAS was a known dsDNA sensor that recognized dsDNA to induced various forms of cell death via the cGAS-STING signal transduction [77][78][79]. Activating transcription factor 3 (ATF3), a common stress sensor, has been reported to promote ferroptosis by directly inhibiting SLC7A11 to reduce GSH levels in cells [80,81]. ...
Background:
Crush syndrome (CS) is a kind of traumatic and ischemic injury that seriously threatens life after prolonged compression. It is characterized by systemic inflammatory reaction, myoglobinuria, hyperkalemia and acute kidney injury (AKI). Especially AKI, it is the leading cause of death from CS. There are various cell death forms in AKI, among which ferroptosis is a typical form of cell death. However, the role of ferroptosis has not been fully revealed in CS-AKI.
Aim of review:
This review aimed to summarize the evidence of ferroptosis in CS-AKI and its related molecular mechanism, discuss the therapeutic significance of ferroptosis in CS-AKI, and open up new ideas for the treatment of CS-AKI.
Key scientific concepts of review:
One of the main pathological manifestations of CS-AKI is renal tubular epithelial cell dysfunction and cell death, which has been attributed to massive deposition of myoglobin. Large amounts of myoglobin released from damaged muscle deposited in the renal tubules, impeding the normal renal tubules function and directly damaging the tubules with oxidative stress and elevated iron levels. Lipid peroxidation damage and iron overload are the distinguishing features of ferroptosis. Moreover, high levels of pro-inflammatory cytokines and damage-associated molecule pattern molecules (HMGB1, double-strand DNA, and macrophage extracellular trap) in renal tissue have been shown to promote ferroptosis. However, how ferroptosis occurs in CS-AKI and whether it can be a therapeutic target remains unclear. In our current work, we systematically reviewed the occurrence and underlying mechanism of ferroptosis in CS-AKI.
Ankyrin repeat and LEM domain-containing 2 (ANKLE2) is a scaffolding protein with established roles in cell division and development, the dysfunction of which is increasingly implicated in human disease. ANKLE2 regulates nuclear envelope disassembly at the onset of mitosis and its reassembly after chromosome segregation. ANKLE2 dysfunction is associated with abnormal nuclear morphology and cell division. It regulates the nuclear envelope by mediating protein-protein interactions with barrier to autointegration factor (BANF1; also known as BAF) and with the kinase and phosphatase that modulate the phosphorylation state of BAF. In brain development, ANKLE2 is crucial for proper asymmetric division of neural progenitor cells. In humans, pathogenic loss-of-function mutations in ANKLE2 are associated with primary congenital microcephaly, a condition in which the brain is not properly developed at birth. ANKLE2 is also linked to other disease pathologies, including congenital Zika syndrome, cancer and tauopathy. Here, we review the molecular roles of ANKLE2 and the recent literature on human diseases caused by its dysfunction.
Zinc finger protein 335 (ZNF335) plays a crucial role in the methylation and, consequently, regulates the expression of a specific set of genes. Variants of the ZNF335 gene have been identified as risk factors for microcephaly in a variety of populations worldwide. Meanwhile, ZNF335 has also been identified as an essential regulator of T-cell development. However, an in-depth understanding of the role of ZNF335 in brain development and T cell maturation is still lacking. In this review, we summarize current knowledge of the molecular mechanisms underlying the involvement of ZNF335 in neuronal and T cell development across a wide range of pre-clinical, post-mortem, ex vivo, in vivo, and clinical studies. We also review the current limitations regarding the study of the pathophysiological functions of ZNF335. Finally, we hypothesize a potential role for ZNF335 in brain disorders and discuss the rationale of targeting ZNF335 as a therapeutic strategy for preventing brain disorders.
Zinc finger protein 335 (Zfp335) is a transcription factor that regulates mammalian neurogenesis and neuronal differentiation. It is a causative factor for severe microcephaly, small somatic size, and neonatal death. Here, we evaluated the effects of Zfp335 in the adult mouse brain after lipopolysaccharide (LPS) challenge. We used wild-type (WT) and Zfp335 knock-down (Zfp335+/- ) mice with LPS administered in the intracerebral ventricle in vivo and cultured microglia treated with LPS in vitro. The impact of Zfp335 was evaluated by RT-PCR, RNA-sequencing, western blotting, immunocytochemistry, ELISA, and the memory behavior tests. Knockdown of Zfp335 expression ameliorated microglia activation significantly, including reduced mRNA and protein expression of Iba1, reduced numbers of microglia, reduced cell diameter, and increased branch length, in the brains of 2-month-old mice after LPS treatment. Zfp335 was expressed in microglia and neurons, but increased in microglia, not neurons, in the brain of mice after LPS administration. LPS-induced microglia-mediated neurodegeneration was dependent upon microglial Zfp335 controlled by nuclear factor-kappa B. Microglial Zfp335 affected neuronal activity through transcriptional regulation of lymphocyte antigen-6M (Ly6M). Our data suggest that Zfp335 is a key transcription factor that exacerbates microglia-mediated neurodegeneration through upregulation of Ly6M expression. Inhibition of microglial Zfp335 may be a new strategy for preventing brain disease induced by microglia activation.
The cyclic GMP-AMP synthase stimulator (cGAS)-stimulator of interferon gene (STING) signaling pathway has an integral role in the host immune response through DNA sensing followed by inducing a robust innate immune defense program. STING has become a promising therapeutic target associated with multiple diseases, including various inflammatory diseases, cancer, and infectious diseases, among others. Thus, modulators of STING are regarded as emerging therapeutic agents. Recent progress has been made in STING research, including recently identified STING-mediated regulatory pathways, the development of a new STING modulator, and the new association of STING with disease. In this review, we focus on recent trends in the development of STING modulators, including structures, mechanisms, and clinical application. Teaser: The structures, mechanisms of action, and clinical application of STING modulators, both agonists and antagonists, are comprehensively reviewed and summarized, as well as the challenges and future perspectives for STING modulator development.
T cells are crucial for immune functions to maintain health and prevent disease. T cell development occurs in a stepwise process in the thymus and mainly generates CD4+ and CD8+ T cell subsets. Upon antigen stimulation, naïve T cells differentiate into CD4+ helper and CD8+ cytotoxic effector and memory cells, mediating direct killing, diverse immune regulatory function, and long-term protection. In response to acute and chronic infections and tumors, T cells adopt distinct differentiation trajectories and develop into a range of heterogeneous populations with various phenotype, differentiation potential, and functionality under precise and elaborate regulations of transcriptional and epigenetic programs. Abnormal T-cell immunity can initiate and promote the pathogenesis of autoimmune diseases. In this review, we summarize the current understanding of T cell development, CD4+ and CD8+ T cell classification, and differentiation in physiological settings. We further elaborate the heterogeneity, differentiation, functionality, and regulation network of CD4+ and CD8+ T cells in infectious disease, chronic infection and tumor, and autoimmune disease, highlighting the exhausted CD8+ T cell differentiation trajectory, CD4+ T cell helper function, T cell contributions to immunotherapy and autoimmune pathogenesis. We also discuss the development and function of γδ T cells in tissue surveillance, infection, and tumor immunity. Finally, we summarized current T-cell-based immunotherapies in both cancer and autoimmune diseases, with an emphasis on their clinical applications. A better understanding of T cell immunity provides insight into developing novel prophylactic and therapeutic strategies in human diseases.
