Reducing FKBP51 Expression in the Ventral Hippocampus Decreases Auditory Fear Conditioning in Male Rats.

Fear conditioning evokes a physiologic release of glucocorticoids that assists learning. As a cochaperone in the glucocorticoid receptor complex, FKBP51 modulates stress-induced glucocorticoid signaling and may influence conditioned fear responses. This study combines molecular and behavioral approaches to examine whether locally reducing FKBP51 expression in the ventral hippocampus is sufficient to affect fear-related behaviors. We hypothesized that reducing FKBP51 expression in the VH would increase glucocorticoid signaling to alter auditory fear conditioning. Adult male rats were injected with an adeno-associated virus (AAV) vector expressing short hairpin - RNAs (shRNA) targeting FKBP5 into the ventral hippocampus to reduce FKBP5 levels or a control AAV. Infusion of FKBP5-shRNA into the ventral hippocampus decreased auditory fear acquisition and recall. Although animals injected with FKBP5-shRNA showed less freezing during extinction recall, the difference was due to a reduced fear recall rather than improved extinction. Reducing ventral hippocampus FKBP51 did not affect exploratory behavior in either the open field test or the elevated zero maze test but did increase passive behavior in the forced swim test, suggesting that the reduction in auditory fear recall was not due to more active responses to acute stress. Furthermore, lower ventral hippocampus FKBP51 levels did not alter corticosterone release in response to restraint stress, suggesting that the reduced fear recall was not due to lower corticosterone release. Our findings suggest FKBP51 in the ventral hippocampus plays a selective role in modulating fear-learning processes and passive behavioral responses to acute stress rather than hypothalamic-pituitary-adrenal axis reactivity or exploratory responses.

FKBP3, a poor prognostic indicator, promotes the progression of LUAD via regulating ferroptosis and immune infiltration.

BACKGROUND: Ferroptosis was reported to possess the therapeutic potentials in various human cancers. In the present study, we explored the expression, clinical significance and the molecular mechanism of FK506 binding protein 3 (FKBP3) in the progression of lung adenocarcinoma (LUAD). MATERIAL AND METHOD: Cox regression was performed to obtain the prognosis related to differentially expressed genes (DEGs) in LUAD datasets from TCGA. We also downloaded the ferroptosis-related gene datasets from GeneCards. Venn diagram was performed to find the intersecting genes and FKBP3 was selected as the targeted gene by analyzing the diagnostic and prognostic values of Top10 intersecting genes. Moreover, univariate and multivariate analyses were performed to evaluate the association between clinicopathological factors and survival rates. GO/KEGG and GSEA analysis was performed to explore the function of FKBP3 in LUAD progression. Protein-protein interaction (PPI) network was performed via STRING database and the top10 hub genes were selected. Finally, the relationship between FKBP3 and immune infiltration was explored by ssGSEA analysis. RESULTS: Firstly, 184 genes associated with the prognosis of LUAD and ferroptosis were obtained. FKBP3 was found to be significantly associated with a poor overall survival rate of LUAD patients. Immunohistochemical staining results showed that FKBP3 was highly located in cytoplasm and membrane of cells in LUAD tissues. PPI network analysis results showed that HDAC1, YY1, HDAC2, MTOR, PSMA3, PIN1, NCL, C14orf166, PIN4, and LARP6 were the top10 hub genes. Furthermore, spearman analysis results showed that the expression of FKBP3 was positively correlated with the abundance of Th2 cells and T helper cells. CONCLUSION: High level of FKBP3 was associated with poor prognostic outcomes of LUAD patients, which also inhibited immune infiltration in LUAD tissues. Additionally, FKBP3 was involved in regulating the ferroptosis process in LUAD patients. Thus, FKBP3 possessed the tumor promotion role might be involving in regulating ferroptosis and immune infiltration in LUAD progression.

FKBP51 is involved in LPS-induced microglial activation via NF-κB signaling to mediate neuroinflammation.

AIMS: FKBP5 encodes FKBP51, which has been implicated in stress-related psychiatric disorders, and its expression is often increased under chronic stress, contributing to mental dysfunctions. However, the precise role of FKBP51 in brain inflammation remains unclear. This study aimed to investigate the role of FKBP51 in microglia-mediated inflammatory responses in the central nervous system. MAIN METHODS: We employed a peripheral lipopolysaccharide (LPS) administration model to compare microglial activation and cytokine gene expression between Fkbp5 knockout (Fkbp5-KO) and wild-type (WT) male mice. Additionally, we used both BV2 and primary microglia in vitro to examine how Fkbp5 deletion influenced inflammation-related pathways and microglial functions. KEY FINDINGS: This study revealed that systemic LPS-induced microglial activation was significantly attenuated in Fkbp5-KO mice compared with WT mice. In Fkbp5-KO mice following the LPS challenge, there was a notable decrease in the expression of pro-inflammatory genes, coupled with an increase in the anti-inflammatory gene Arg1. Furthermore, Fkbp5 knockdown in BV2 microglial cells led to reduced expression of LPS-induced inflammatory markers, and targeted inhibition of NF-κB activation, while Akt signaling remained unaffected. Similar results were observed in Fkbp5-KO primary microglia, which exhibited not only decreased microglial activation but also a significant reduction in phagocytic activity in response to LPS stimulation. SIGNIFICANCE: This study highlights the critical role of FKBP51 in LPS-induced microglial activation and neuroinflammation. It shows that reducing FKBP51 levels attenuates inflammation through NF-κB signaling in microglia. This suggests that FKBP51 is a potential target for alleviating neuroinflammation-induced stress responses.

Single-nucleus transcriptome analysis identifies a novel FKBP5+ endothelial cell subtype involved in endothelial-to-mesenchymal transition in adipose tissue during aging.

Age-associated adipose tissue (AT) dysfunction is multifactorial and often leads to detrimental health consequences. AT is highly vascularized and endothelial cells (ECs) has been recently identified as a key regulator in the homeostasis of AT. However, the alteration of cell composition in AT during aging and the communication between endothelial cells and adipocytes remain poorly understood. In this study, we take advantage of single nucleus RNA sequencing analysis, and discovered a group of FKBP5+ ECs specifically resident in aged AT. Of interest, FKBP5+ ECs exhibited the potential for endothelial-to-mesenchymal transition (EndoMT) and exhibited a critical role in regulating adipocytes. Furthermore, lineage tracing experiments demonstrated that ECs in aged AT tend to express FKBP5 and undergo EndoMT with progressive loss of endothelial marker. This study may provide a basis for a new mechanism of microvascular ECs-induced AT dysfunction during aging.

NFAT activation by FKBP52 promotes cancer cell proliferation by suppressing p53.

FK506-binding protein 52 (FKBP52) is a member of the FKBP family of proline isomerases. FKBP52 is up-regulated in various cancers and functions as a positive regulator of steroid hormone receptors. Depletion of FKBP52 is known to inhibit cell proliferation; however, the detailed mechanism remains poorly understood. In this study, we found that FKBP52 depletion decreased MDM2 transcription, leading to stabilization of p53, and suppressed cell proliferation. We identified NFATc1 and NFATc3 as transcription factors that regulate MDM2 We also found that FKBP52 associated with NFATc3 and facilitated its nuclear translocation. In addition, calcineurin, a well-known Ca2+ phosphatase essential for activation of NFAT, plays a role in MDM2 transcription. Supporting this notion, MDM2 expression was found to be regulated by intracellular Ca2+ Taken together, these findings reveal a new role of FKBP52 in promoting cell proliferation via the NFAT-MDM2-p53 axis, and indicate that inhibition of FKBP52 could be a new therapeutic tool to activate p53 and inhibit cell proliferation.

The Role of FKBPs in Complex Disorders: Neuropsychiatric Diseases, Cancer, and Type 2 Diabetes Mellitus.

Stress is a common denominator of complex disorders and the FK-506 binding protein (FKBP)51 plays a central role in stress. Hence, it is not surprising that multiple studies imply the involvement of the FKBP51 protein and/or its coding gene, FKBP5, in complex disorders. This review summarizes such reports concentrating on three disorder clusters-neuropsychiatric, cancer, and type 2 diabetes mellitus (T2DM). We also attempt to point to potential mechanisms suggested to mediate the effect of FKBP5/FKBP51 on these disorders. Neuropsychiatric diseases considered in this paper include (i) Huntington's disease for which increased autophagic cellular clearance mechanisms related to decreased FKBP51 protein levels or activity is discussed, Alzheimer's disease for which increased FKBP51 activity has been shown to induce Tau phosphorylation and aggregation, and Parkinson's disease in the context of which FKBP12 is mentioned; and (ii) mental disorders, for which significant association with the single nucleotide polymorphism (SNP) rs1360780 of FKBP5 intron 7 along with decreased DNA methylation were revealed. Since cancer is a large group of diseases that can start in almost any organ or tissue of the body, FKBP51's role depends on the tissue type and differences among pathways expressed in those tumors. The FKBP51-heat-shock protein-(Hsp)90-p23 super-chaperone complex might function as an oncogene or as a tumor suppressor by downregulating the serine/threonine protein kinase (AKt) pathway. In T2DM, two potential pathways for the involvement of FKBP51 are highlighted as affecting the pathogenesis of the disease-the peroxisome proliferator-activated receptor-γ (PPARγ) and AKt.

Multi-omics in nasal epithelium reveals three axes of dysregulation for asthma risk in the African Diaspora populations.

Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1, was downregulated in cases (q = 3.26 × 10-9) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response (CEACAM5; p = 9.62 × 10-16 and CPA3; p = 2.39 × 10-14) and wound healing (FN1; p = 7.63 × 10-9). Multi-omic analysis identifies FKBP5, a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes - increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response - that may play a critical role in asthma within the African Diaspora.

Integrating Explicit and Implicit Fullerene Models into UNRES Force Field for Protein Interaction Studies.

Fullerenes, particularly C60, exhibit unique properties that make them promising candidates for various applications, including drug delivery and nanomedicine. However, their interactions with biomolecules, especially proteins, remain not fully understood. This study implements both explicit and implicit C60 models into the UNRES coarse-grained force field, enabling the investigation of fullerene-protein interactions without the need for restraints to stabilize protein structures. The UNRES force field offers computational efficiency, allowing for longer timescale simulations while maintaining accuracy. Five model proteins were studied: FK506 binding protein, HIV-1 protease, intestinal fatty acid binding protein, PCB-binding protein, and hen egg-white lysozyme. Molecular dynamics simulations were performed with and without C60 to assess protein stability and investigate the impact of fullerene interactions. Analysis of contact probabilities reveals distinct interaction patterns for each protein. FK506 binding protein (1FKF) shows specific binding sites, while intestinal fatty acid binding protein (1ICN) and uteroglobin (1UTR) exhibit more generalized interactions. The explicit C60 model shows good agreement with all-atom simulations in predicting protein flexibility, the position of C60 in the binding pocket, and the estimation of effective binding energies. The integration of explicit and implicit C60 models into the UNRES force field, coupled with recent advances in coarse-grained modeling and multiscale approaches, provides a powerful framework for investigating protein-nanoparticle interactions at biologically relevant scales without the need to use restraints stabilizing the protein, thus allowing for large conformational changes to occur. These computational tools, in synergy with experimental techniques, can aid in understanding the mechanisms and consequences of nanoparticle-biomolecule interactions, guiding the design of nanomaterials for biomedical applications.

Antascomicin B stabilizes FKBP51-Akt1 complexes as a molecular glue.

Antascomicin B is a natural product that similarly to the macrolides FK506 and Rapamycin binds to the FK506-binding protein 12 (FKBP12). FK506 and Rapamycin act as molecular glues by inducing ternary complexes between FKBPs and additional target proteins. Whether Antascomicin B can induce ternary complexes is unknown. Here we show that Antascomicin B binds tightly to larger human FKBP homologs. The cocrystal structure of FKBP51 in complex with Antascomicin B revealed that large parts of Antascomicin B are solvent-exposed and available to engage additional proteins. Cellular studies demonstrated that Antascomicin B enhances the interaction between human FKBP51 and human Akt. Our studies show that molecules with molecular glue-like properties are more prominent in nature than previously thought. We predict the existence of additional 'orphan' molecular glues that evolved to induce ternary protein complexes but where the relevant ternary complex partners are unknown.

The FKBP51s Splice Isoform Predicts Unfavorable Prognosis in Patients with Glioblastoma.

The primary treatment for glioblastoma (GBM) is removing the tumor mass as defined by MRI. However, MRI has limited diagnostic and predictive value. Tumor-associated macrophages (TAM) are abundant in GBM tumor microenvironment (TME) and are found in peripheral blood (PB). FKBP51 expression, with its canonical and spliced isoforms, is constitutive in immune cells and aberrant in GBM. Spliced FKBP51s supports M2 polarization. To find an immunologic signature that combined with MRI could advance in diagnosis, we immunophenotyped the macrophages of TME and PB from 37 patients with GBM using FKBP51s and classical M1-M2 markers. We also determined the tumor levels of FKBP51s, PD-L1, and HLA-DR. Tumors expressing FKBP51s showed an increase in various M2 phenotypes and regulatory T cells in PB, indicating immunosuppression. Tumors expressing FKBP51s also activated STAT3 and were associated with reduced survival. Correlative studies with MRI and tumor/macrophages cocultures allowed to interpret TAMs. Tumor volume correlated with M1 infiltration of TME. Cocultures with spheroids produced M1 polarization, suggesting that M1 macrophages may infiltrate alongside cancer stem cells. Cocultures of adherent cells developed the M2 phenotype CD163/FKBP51s expressing pSTAT6, a transcription factor enabling migration and invasion. In patients with recurrences, increased counts of CD163/FKBP51s monocyte/macrophages in PB correlated with callosal infiltration and were accompanied by a concomitant decrease in TME-infiltrating M1 macrophages. PB PD-L1/FKBP51s connoted necrotic tumors. In conclusion, FKBP51s identifies a GBM subtype that significantly impairs the immune system. Moreover, FKBP51s marks PB macrophages associated with MRI features of glioma malignancy that can aid in patient monitoring. SIGNIFICANCE: Our research suggests that by combining imaging with analysis of monocyte/macrophage subsets in patients with GBM, we can enhance our understanding of the disease and assist in its treatment. We discovered a similarity in the macrophage composition between the TME and PB, and through association with imaging, we could interpret macrophages. In addition, we identified a predictive biomarker that drew more attention to immune suppression of patients with GBM.

Structure-based discovery of small molecule inhibitors of FKBP51-Hsp90 protein-protein interaction.

The heat shock protein 90 kDa (Hsp90) molecular chaperone machinery is responsible for the folding and activation of hundreds of important clients such as kinases, steroid hormone receptors, transcription factors, etc. This process is dynamically regulated in an ATP-dependent manner by Hsp90 co-chaperones including a group of tetratricopeptide (TPR) motif proteins that bind to the C-terminus of Hsp90. Among these TPR containing co-chaperones, FK506-binding protein 51 kDa (FKBP51) is reported to play an important role in stress-related pathologies, psychiatric disorders, Alzheimer's disease, and cancer, making FKBP51-Hsp90 interaction a potential therapeutic target. In this study, we report identification of potent and selective inhibitors of FKBP51-Hsp90 protein-protein interaction using a structure-based virtual screening approach. Upon in vitro evaluation, the identified hits show a considerable degree of selectivity towards FKBP51 over other TPR proteins, particularly for highly homologous FKBP52. Tyr355 of FKBP51 emerged as an important contributor to inhibitor's specificity. Additionally, we demonstrate the impact of these inhibitors on cellular energy metabolism, and neurite outgrowth, which are subjects of FKBP51 regulation. Overall, the results from this study highlight a novel pharmacological approach towards regulation of FKBP51 function and more generally, Hsp90 function via its interaction with TPR co-chaperones.

Chronic adolescent stress alters GR-FKBP5 interactions in the hippocampus of adult female rats.

Chronic stress exposure during development can have lasting behavioral consequences that differ in males and females. More specifically, increased depressive behaviors in females, but not males, are observed in both humans and rodent models of chronic stress. Despite these known stress-induced outcomes, the molecular consequences of chronic adolescent stress in the adult brain are less clear. The stress hormone corticosterone activates the glucocorticoid receptor, and activity of the receptor is regulated through interactions with co-chaperones-such as the immunophilin FK506 binding proteins 5 (FKBP5). Previously, it has been reported that the adult stress response is modified by a history of chronic stress; therefore, the current study assessed the impact of chronic adolescent stress on the interactions of the glucocorticoid receptor (GR) with its regulatory co-chaperone FKBP5 in response to acute stress in adulthood. Although protein presence for FKBP5 did not differ by group, assessment of GR-FKBP5 interactions demonstrated that adult females with a history of chronic adolescent stress had elevated GR-FKBP5 interactions in the hippocampus following an acute stress challenge which could potentially contribute to a reduced translocation pattern given previous literature describing the impact of FKBP5 on GR activity. Interestingly, the altered co-chaperone interactions of the GR in the stressed female hippocampus were not coupled to an observable difference in transcription of GR-regulated genes. Together, these studies show that chronic adolescent stress causes lasting changes to co-chaperone interactions with the glucocorticoid receptor following stress exposure in adulthood and highlight the potential role that FKBP5 plays in these modifications. Understanding the long-term implications of adolescent stress exposure will provide a mechanistic framework to guide the development of interventions for adult disorders related to early life stress exposures.

The high FKBP1A expression in WBCs as a potential screening biomarker for pancreatic cancer.

Given the limitation of current routine approaches for pancreatic cancer screening and detection, the mortality rate of pancreatic cancer cases is still critical. The development of blood-based molecular biomarkers for pancreatic cancer screening and early detection which provide less-invasive, high-sensitivity, and cost-effective, is urgently needed. The goal of this study is to identify and validate the potential molecular biomarkers in white blood cells (WBCs) of pancreatic cancer patients. Gene expression profiles of pancreatic cancer patients from NCBI GEO database were analyzed by CU-DREAM. Then, mRNA expression levels of three candidate genes were determined by quantitative RT-PCR in WBCs of pancreatic cancer patients (N = 27) and healthy controls (N = 51). ROC analysis was performed to assess the performance of each candidate gene. A total of 29 upregulated genes were identified and three selected genes were performed gene expression analysis. Our results revealed high mRNA expression levels in WBCs of pancreatic cancer patients in all selected genes, including FKBP1A (p < 0.0001), PLD1 (p < 0.0001), and PSMA4 (p = 0.0002). Among candidate genes, FKBP1A mRNA expression level was remarkably increased in the pancreatic cancer samples and also in the early stage (p < 0.0001). Moreover, FKBP1A showed the greatest performance to discriminate patients with pancreatic cancer from healthy individuals than other genes with the 88.9% sensitivity, 84.3% specificity, and 90.1% accuracy. Our findings demonstrated that the alteration of FKBP1A gene in WBCs serves as a novel valuable biomarker for patients with pancreatic cancer. Detection of FKBP1A mRNA expression level in circulating WBCs, providing high-sensitive, less-invasive, and cost-effective, is simple and feasible for routine clinical setting that can be applied for pancreatic cancer screening and early detection.

DNA methylation patterns of FKBP5 regulatory regions in brain and blood of humanized mice and humans.

Humanized mouse models can be used to explore human gene regulatory elements (REs), which frequently lie in non-coding and less conserved genomic regions. Epigenetic modifications of gene REs, also in the context of gene x environment interactions, have not yet been explored in humanized mouse models. We applied high-accuracy measurement of DNA methylation (DNAm) via targeted bisulfite sequencing (HAM-TBS) to investigate DNAm in three tissues/brain regions (blood, prefrontal cortex and hippocampus) of mice carrying the human FK506-binding protein 5 (FKBP5) gene, an important candidate gene associated with stress-related psychiatric disorders. We explored DNAm in three functional intronic glucocorticoid-responsive elements (at introns 2, 5, and 7) of FKBP5 at baseline, in cases of differing genotype (rs1360780 single nucleotide polymorphism), and following application of the synthetic glucocorticoid dexamethasone. We compared DNAm patterns in the humanized mouse (N = 58) to those in human peripheral blood (N = 447 and N = 89) and human postmortem brain prefrontal cortex (N = 86). Overall, DNAm patterns in the humanized mouse model seem to recapitulate DNAm patterns observed in human tissue. At baseline, this was to a higher extent in brain tissue. The animal model also recapitulated effects of dexamethasone on DNAm, especially in peripheral blood and to a lesser extent effects of genotype on DNAm. The humanized mouse model could thus assist in reverse translation of human findings in psychiatry that involve genetic and epigenetic regulation in non-coding elements.

A double inducible cell ablation system for eliminating senescent astrocytes via apoptosis.

PURPOSE: Cell senescence stands as a principal risk factor for various neurodegenerative diseases, with astrocytic senescence emerging as a potentially pivotal player in the pathogenesis of aging and neurodegenerative disorders. Clearing senescent astrocytes holds promise as a potential therapeutic approach for senescence-related diseases. METHODS: In this study, we designed and constructed two plasmids aimed at inducing apoptosis in senescent astrocytes. This was achieved through the ligation of FKBP (FK506-binding protein) and FRB (FKBP and FKBP rapamycin binding domain) and the formation of caspase8 dimers, thereby achieving the purpose of eliminating senescent astrocytes. RESULTS: The developed vector system demonstrates a specifically capability to induce apoptosis in aging astrocytes, offering a targeted approach to eliminate these cells. CONCLUSION: The utilization of the double -inducible suicide gene system provides a versatile tool forstimulating cell apoptosis and inhibiting cellular senescence. This system proves valuable in exploring the intrinsic roles and molecular mechanisms of senescent cells in the occurrence and development of aging-related diseases. Ultimately, it offers a potential avenue for developing an efficient treatment system for such conditions.

GPX4 inhibits apoptosis of thyroid cancer cells through regulating the FKBP8/Bcl-2 axis.

GPX4 has attracted much attention as a key molecule of cell ferroptosis, but its role in cell apoptosis is rarely reported, and its role in apoptosis of thyroid cancer (TC) cell has not been reported. The analysis of TCGA database showed that both GPX4 and FKBP8 were highly expressed in TC tumor tissues; The expression of GPX4 and FKBP8 were positively correlated. The immunohistochemical analysis further confirmed that GPX4 and FKBP8 were highly expressed in TC tumor tissues. In addition, the high expression of GPX4 and FKBP8 were both significantly correlated with the poor prognosis of TC. Silencing GPX4 significantly inhibited the proliferation, induced apoptosis of TC cells, and reduced tumor growth in mice. The co-immunoprecipitation assay revealed a physical interaction between GPX4 and FKBP8 observed in the TC cells. Knockdown of FKBP8 significantly inhibited the proliferation and induced apoptosis of TC cells. Rescue experiments suggested that knockdown of FKBP8 could reverse the strengthens of cell proliferation and apoptosis and the higher expression of FKBP8 and Bcl-2 caused by overexpression of GPX4. Our results suggest that the GPX4/FKBP8/Bcl-2 axis promotes TC development by inhibiting TC cell apoptosis, which provides potential molecular targets for TC therapeutic strategies.

FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation.

Renal cell carcinoma (RCC) is one of the three major malignant tumors of the urinary system and originates from proximal tubular epithelial cells. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of RCC cases and is recognized as a metabolic disease driven by genetic mutations and epigenetic alterations. Through bioinformatic analysis, we found that FK506 binding protein 10 (FKBP10) may play an essential role in hypoxia and glycolysis pathways in ccRCC progression. Functionally, FKBP10 promotes the proliferation and metastasis of ccRCC in vivo and in vitro depending on its peptidyl-prolyl cis-trans isomerase (PPIase) domains. Mechanistically, FKBP10 binds directly to lactate dehydrogenase A (LDHA) through its C-terminal region, the key regulator of glycolysis, and enhances the LDHA-Y10 phosphorylation, which results in a hyperactive Warburg effect and the accumulation of histone lactylation. Moreover, HIFα negatively regulates the expression of FKBP10, and inhibition of FKBP10 enhances the antitumor effect of the HIF2α inhibitor PT2385. Therefore, our study demonstrates that FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to HIF2α blockade by facilitating LDHA phosphorylation, which may be exploited for anticancer therapy.

FKBP38 suppresses endometrial cancer cell proliferation and metastasis by inhibiting the mTOR pathway.

Endometrial cancer (EC) is a common gynecological malignancy, and advanced-stage or recurrent EC is associated with a high mortality rate owing to the ineffectiveness of currently available treatments. FK506-binding protein 38 (FKBP38) is a member of the immunophilin family and inhibits melanoma and breast cancer cell metastasis. However, the functions of FKBP38 and its potential mechanism in EC remain unclear. Herein, we analyzed the expression levels of FKBP38 in EC cells and found that the FKBP38 expression was high in Ishikawa cells, and low in AN3CA cells, traditionally considered a low grade and a high grade cell line, respectively, in pathology classification. Moreover, FKBP38 inhibited cell proliferation, migration and invasion in EC cells, FKBP38 knockdown significantly promoted tumor growth of Ishikawa cells in a subcutaneous xenograft model and increased the number of lung metastases of Hec-1-A cells in a metastatic mouse model. Furthermore, FKBP38 suppressed several target proteins of epithelial-to-mesenchymal transition (EMT) and reduced the phosphorylation of ribosomal S6 protein (S6), eukaryotic initiation factor 4E-binding protein 1 (4EBP-1), indicating the potent inhibition of the mammalian target of rapamycin (mTOR) pathway. Meanwhile, the inhibition of mTOR neutralized the elevation of EC cell proliferation, migration and invasion after FKBP38 knockdown. In summary, FKBP38 would exert a tumor-suppressing role by modulating the mTOR pathway. Our results indicate that FKBP38 may be considered as a factor of EC metastasis and a new target for EC therapeutic intervention.

FKBP51-Hsp90 Interaction-Deficient Mice Exhibit Altered Endocrine Stress Response and Sex Differences Under High-Fat Diet.

FK506-binding protein 51 kDa (FKBP51), encoded by Fkbp5 gene, gained considerable attention as an important regulator of several aspects of human biology including stress response, metabolic dysfunction, inflammation, and age-dependent neurodegeneration. Its catalytic peptidyl-prolyl isomerase (PPIase) activity is mediated by the N-terminal FK506-binding (FK1) domain, whereas the C-terminal tetratricopeptide motif (TPR) domain is responsible for FKBP51 interaction with molecular chaperone heat shock protein 90 (Hsp90). To understand FKBP51-related biology, several mouse models have been created. These include Fkbp5 complete and conditional knockouts, overexpression, and humanized models. To dissect the role of FKBP51-Hsp90 interaction in FKBP51 biology, we have created an interaction-deficient mouse (Fkbp5TPRmut) by introducing two-point mutations in the TPR domain of FKBP51. FKBP51-Hsp90 interaction-deficient mice are viable, fertile and show Mendelian inheritance. Intracellular association of FKBP51 with Hsp90 is significantly reduced in homozygous mutants compared to wild-type animals. No behavioral differences between genotypes were seen at 2 months of age, however, sex-dependent differences were detected in Y-maze and fear conditioning tests at the age of 12 months. Moreover, we have found a significant reduction in plasma levels of corticosterone and adrenocorticotropic hormone in Fkbp5TPRmut mice after acute stress. In contrast to Fkbp5 knockout mice, females of Fkbp5TPRmut showed increased body weight gain under high-fat diet treatment. Our data confirm the importance of FKBP51-Hsp90 interactions for stress-related endocrine signaling. Also, Fkbp5TPRmut mice can serve as a useful in vivo tool to discriminate between Hsp90-dependent and independent functions of FKBP51.

Dynamics of mRNA fate during light stress and recovery: from transcription to stability and translation.

Transcript stability is an important determinant of its abundance and, consequently, translational output. Transcript destabilisation can be rapid and is well suited for modulating the cellular response. However, it is unclear the extent to which RNA stability is altered under changing environmental conditions in plants. We previously hypothesised that recovery-induced transcript destabilisation facilitated a phenomenon of rapid recovery gene downregulation (RRGD) in Arabidopsis thaliana (Arabidopsis) following light stress, based on mathematical calculations to account for ongoing transcription. Here, we test this hypothesis and investigate processes regulating transcript abundance and fate by quantifying changes in transcription, stability and translation before, during and after light stress. We adapt syringe infiltration to apply a transcriptional inhibitor to soil-grown plants in combination with stress treatments. Compared with measurements in juvenile plants and cell culture, we find reduced stability across a range of transcripts encoding proteins involved in RNA binding and processing. We also observe light-induced destabilisation of transcripts, followed by their stabilisation during recovery. We propose that this destabilisation facilitates RRGD, possibly in combination with transcriptional shut-off that was confirmed for HSP101, ROF1 and GOLS1. We also show that translation remains highly dynamic over the course of light stress and recovery, with a bias towards transcript-specific increases in ribosome association, independent of changes in total transcript abundance, after 30 min of light stress. Taken together, we provide evidence for the combinatorial regulation of transcription and stability that occurs to coordinate translation during light stress and recovery in Arabidopsis.