ATF5 activates LPAR5 to enhance macrophage pro-inflammatory responses to exacerbate rheumatoid arthritis.

Dietary phospholipids alleviate high fat diet-induced intestinal lipid deposition through ATF4-PPARα-MTTP/SAR1B pathway in yellow catfish.

ATF5-mediated mitochondrial UPR inhibited RANKL in Porphyromonas gingivalis LPS-treated osteoblasts.

The PERK-eIF2α branch activates the NLRP3 inflammasome through the NF-κB signaling pathway to suppress NDV replication.

Capsaicin attenuates methylglyoxal-induced neurotoxicity via the ATF4-Sestrin2 signaling and direct scavenging of methylglyoxal.

CD8+ T cell exhaustion limits the immune response to tumors because of ineffective T cell effector functions. Thus, therapies that inhibit T-cell exhaustion are critical for optimizing cancer treatment. Recent studies have implicated epigenetic proteins in T-cell exhaustion. Here, we identified activating transcription factor 7 interacting protein (ATF7ip) as an epigenetic protein critical for inducing T cell exhaustion. Loss of Atf7ip in CD8+ T cells resulted in decreased terminal exhaustion and increased numbers of progenitor-exhausted cells in both chronic viral infections and cancer. Given the decreased T cell terminal exhaustion observed with Atf7ip-deficiency in CD8+ T cells, this may be one mechanism that leads to decreased tumor burden. Mechanistically, ATF7ip functions to stimulate the deposition of repressive H3K9me3 at critical immune-effector gene loci, such as Il7r and Il2 leading to enhanced exhaustion. Our data suggest that ATF7ip may be a rational target for deletion in adoptive T-cell therapies to reduce CD8+ T-cell exhaustion.

Acute kidney injury (AKI), whether induced by nephrotoxins like glycerol or by gamma radiation, is characterized by severe oxidative stress and subsequent mitochondrial dysfunction. We investigated the protective mechanism of sodium propionate (SP) against AKI in a rat model. Six experimental groups were established: (I) control rats were given saline; (II) rats were administered SP (37.5mg/kg, p.o.) for two weeks; (III) rats were given an intramuscular injection of glycerol 10 mL/kg body weight; (IV) rats were given glycerol followed by SP treatment for two weeks; (V) rats were exposed to fractionated gamma-radiation (8Gy; delivered as 2Gy x 4 times); and (VI) γ-irradiated rats were treated with SP for two weeks. In comparison to AKI rats, SP treatment significantly preserved renal function, reduced serum urea and creatinine, and improved histopathological features. Biochemically, SP reduced lipid peroxidation and protein oxidation (malondialdehyde MDA, protein carbonyl PC, and lipofuscin) while restoring antioxidant defenses as reduced glutathione (GSH) and methionine sulfoxide reductase A (MSRA). SP restored mitophagy flux by increasing microtubule-associated protein light chain 3 (LC3II/LC3I) ratio and PTEN-induced putative kinase 1 (PINK-1) levels, promoting p62 clearance, and downregulating the mitochondrial stress marker, activating transcription factor 5 (ATF5), relative to the untreated AKI groups. These findings demonstrate that SP confers protection against AKI by attenuating oxidative stress and re-establishing mitochondrial quality control through re-establishment of autophagic flux. Hence, SP represents a promising candidate for therapeutic intervention in nephrotoxin- and γ-radiation-induced renal injury.

AHSA1-DNAJB4 axis: A regulatory mechanism that initiates the ERAD pathway to facilitate endometrial cancer progression.

Traumatic brain injury (TBI) is a leading cause of long-term disabilities and mortality worldwide. Blast-induced TBI (bTBI) is the injury most commonly sustained by military personnel, but the pathomechanisms are largely unknown. Recently, accumulating evidence has suggested that neuroinflammation, characterized by the activation of microglia and astrocytes and elevated production of inflammatory mediators such as interleukins, cytokines, and chemotactic cytokines (chemokines), is a key pathological feature in bTBI. Therefore, controlling excessive neuroinflammation is critical to improve long-term neurological outcomes after bTBI, so understanding the mechanism of the neuroinflammation in bTBI is of significant interest. Activating transcription factor 3 (ATF3) is one of the most important transcription factors that regulate local and systemic inflammation in multiple pathophysiological processes such as cardiovascular disease, dementia, and ischemia/reperfusion-induced damage. Recently, ATF3 has attracted much attention for involvement in the neuroinflammatory response, by regulating the production of neuroinflammatory mediators, in a weight-drop-based TBI model. In this model, the upregulation of Atf3 messenger ribonucleic acid (mRNA) levels was rapidly induced with the strongest increase at 1-2 h and decline by 4 h post-injury. However, there is little information about ATF3 in bTBI, and thus, the present study examined the expression of ATF3 in a mouse bTBI model. We here show the significant upregulation of Atf3 mRNA was not observed in the cerebral cortex at 2 h post-exposure. However, the upregulation was observed at 5 days post-injury. Our results suggest robust differences in time course of neuroinflammation between other non-blast and blast TBIs.

Activating transcription factor 2 (ATF2) is a member of the AP-1 superfamily that regulates essential cellular processes through its activity as a nuclear transcription factor. Although ATF2 plays well-established roles in neurodevelopment, inflammation, and cancer, the mechanisms underlying its nuclear localisation remain poorly characterised. Here, we investigate the structural and functional basis of ATF2 nuclear import via the classical importin-α/β1 (IMPα/β1) pathway. Using quantitative in vitro binding assays, we demonstrate that ATF2 interacts with multiple IMPα paralogues. Fluorescence polarisation measurements reveal the highest binding affinity for IMPα1, with progressively weaker interactions observed for IMPα3, IMPα5, and IMPα7. Crystallographic analysis of ATF2 bound to IMPα1 identifies two basic clusters that are important for interaction: site 1 (353EKRRK357), which binds the major site of IMPα1, and site 2 (372KRK374), which binds the minor site. Mutation of key residues confirms the importance of both motifs, with site 1 contributing more substantially to binding. Quantitative confocal laser scanning microscopy analysis in HEK293A cells supports these findings, showing that mutation of both clusters is required to fully abolish ATF2 nuclear localisation. Inhibition of classical nuclear import using Bimax2 significantly reduces nuclear accumulation, whereas treatment with leptomycin B confirms a role of chromosomal region maintenance 1 (CRM1)-mediated nuclear export. Notably, ATF2 mutants incapable of nuclear import can localise to the nucleus when co-expressed with c-Jun, indicating that c-Jun can facilitate ATF2 nuclear import via heterodimerisation. Together, these results establish that ATF2 enters the nucleus through IMPα recognition of two basic clusters and highlight the redundancy and complexity of ATF2 nuclear trafficking mechanisms.

During mammalian evolution, excitatory neurons in upper cortical layer 2and layer 3 (L2/3) have shown a disproportionate expansion compared with other layers1-4. Replicative expansion of cortical neural progenitors is associated with considerable oxidative DNA damage. Here we show that activating transcription factor 4 (ATF4) has roles as a critical regulator of the DNA damage response, directly activating components of double-stranded DNA repair, including CIRBP, UBA52 and EBF1. Notably, pan-cortical knockout (Emx1-Cre;Atf4fl/fl) demonstrates that ATF4 is required specifically for the development of upper layer 2/3 neurons, marked by the expression of cut-like homeobox 2 protein, CUX2. ATF4 functions to repair DNA damage and attenuate cell death of embryonic radial glial progenitors in a p53-dependent manner. In particular, we show that cold inducible RNA-binding protein (CIRBP) is a transcriptional target of ATF4 that is required for normal phosphorylation of the key double-strand DNA repair factor ataxia telangiectasia mutated (ATM). These findings establish that ATF4 is an essential regulator of the DNA damage response. They further indicate that there are extraordinary requirements for DNA repair after replicative stress in CUX2+ neurons during mammalian brain development.

ATF4 in cardiovascular diseases: an emerging therapeutic target.

UFL1 deficiency impairs skeletal muscle development by activating PERK/eIF2α/ATF4/CHOP pathway-dependent apoptosis.

Dairy cows with ketosis display immune dysfunction and a high incidence of infectious diseases, which may partly be attributed to excessive endoplasmic reticulum stress (ERS) and apoptosis in macrophages. The objective of the present study was to assess the role of ERS in macrophage apoptosis of ketotic dairy cows. Compared with healthy cows, the apoptosis number of macrophages and the protein abundance of glucose regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), and activating transcription factor 6 (ATF6); the ratio of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK)/PERK, phosphorylated inositol-requiring enzyme 1 (p-IRE1)/IRE1 and phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α)/eIF2α; and mean fluorescence intensity of C/EBP homology protein (CHOP) were greater in cows with clinically ketosis (CK). Treatment with FFA increased protein abundance of GRP78, CHOP, ATF6 and p-IRE1/IRE1, and mean fluorescence intensity of CHOP. Furthermore, FFA increased the protein abundance of cysteinyl aspartate-specific proteinase-3 (Caspase-3) and mean fluorescence intensity of Caspase-3 but decreased the Bcl-2/Bax protein abundance ratio, which was accompanied by an increase in the number macrophage apoptosis. Inhibition of ERS via TUDCA attenuated the increased macrophage apoptosis and the activated apoptotic pathways induced by Tn or FFA. Thus, hyperphysiological concentrations of FFA induce apoptosis in macrophages by triggering ERS in ketotic dairy cows.

SIRT7 facilitates ferroptosis resistance of melanocytes via activating the SMAD3-ATF3-GPX4 signaling pathway in vitiligo.

Dietary EGCG reshapes metabolic-epigenetic interplay to induce transgenerational host defense.

Group A Streptococcus host-pathogen dual crosstalk.

Macrophage migration inhibitory factor superfamily in tumor metabolism: mechanistic insights and therapeutic potential.

ATF2-LPCAT1-mediated PKM2 acetylation links cholesterol stress to macrophage metabolic reprogramming and functional remodeling.

Neurodegeneration shows regional and cell-type-specific patterns in ageing and disease1, but the underlying mechanisms for cell-type-specific neuronal losses remain poorly understood. Previous studies have shown that upper cortical layer thinning occurs in progressive human multiple sclerosis (MS) and that cortical layer 2and layer3(L2/3) excitatory neurons (L2/3ENs) that express CUT-like homeobox 2 (CUX2) are selectively vulnerable to degeneration2. Here we report that L2/3ENs within MS cortical lesions have an elevated DNA damage burden. DNA damage and selective loss of L2/3ENs were recapitulated in diverse mouse models of demyelination and pan-cortical inflammation, confirming their intrinsic vulnerability. Functions of Cux2 and activating transcription factor 4 (Atf4) were essential for resilience of L2/3ENs during postnatal neuroinflammation, acting in neurons to enhance DNA double-strand break repair. Interferon-γ, a cytokine implicated in MS pathogenesis3,4, was sufficient to elevatelevels of reactive oxygen species, leading to DNAdamage-mediated neuronal death in vitro, and caused selective depletion of L2/3 neurons in mice. These findings indicate that DNA damage burden and inadequate repair in CUX2+ L2/3ENs contributes to selective vulnerability in neuroinflammatory injury.