Regulation Of Export Research Articles

The E3 ubiquitin ligase, HECTD1, is involved in ABCA1-mediated cholesterol export from macrophages

The ABC lipid transporters, ABCA1 and ABCG1, are essential for maintaining lipid homeostasis in cells such as macrophages by exporting excess cholesterol to extracellular acceptors. These transporters are highly regulated at the post-translational level, including protein ubiquitination. Our aim was to investigate the role of the E3 ubiquitin ligase HECTD1, recently identified as associated with ABCG1, on ABCG1 and ABCA1 protein levels and cholesterol export function. Here, we show that HECTD1 protein is widely expressed in a range of human and murine primary cells and cell lines, including macrophages, neuronal cells and insulin secreting β-cells. siRNA knockdown of HECTD1 unexpectedly decreased overexpressed ABCG1 protein levels and cell growth, but increased native ABCA1 protein in CHO-K1 cells. Knockdown of HECTD1 in unloaded THP-1 macrophages did not affect ABCG1 but significantly increased ABCA1 protein levels, in wild-type as well as THP-1 cells that do not express ABCG1. Cholesterol export from macrophages to apoA-I over time was increased after knockdown of HECTD1, however these effects were not sustained in cholesterol-loaded cells. In conclusion, we have identified a new candidate, the E3 ubiquitin ligase HECTD1, that may be involved in the regulation of ABCA1-mediated cholesterol export from unloaded macrophages to apoA-I. The exact mechanism by which this ligase affects this pathway remains to be elucidated.

Heat shock factor 4 regulates the expression of HSP25 and alpha B-crystallin by associating with DEXD/H-box RNA helicase UAP56.

Heat shock factor 4 controls the transcription of small heat shock proteins (e.g., HSP25, alpha B-cyrstallin, and r-crystallin), that play important roles in modulating lens proteostasis. However, the molecular mechanism underlying HSF4-mediated transcription is still unclear. Using yeast two hybrid, we found that HSF4 interacts with the ATP-dependent DEXD/H-box RNA helicase UAP56, and their interaction in lens epithelial cell line was further confirmed by GST-pull down assay. UAP56 is a vital regulator of pre-mRNA splicing and mature mRNA nuclear export. The immunofluorescence assay showed that HSF4 and UBA56 co-localize with each other in the nucleus of lens epithelial cells. Ectopic UAP56 upregulated HSF4-controlled HSP25 and alpha B-crystallin proteins expression, while knocking down UAP56 by shRNA reversed it. Moreover, UAP56 interacts with and facilitates the nuclear exportation of HSP25 and alpha B-crystallin mRNA without impacting their total mRNA expression level. In lens tissues, both UAP56 and HSF4 are expressed in the same nucleus of lens fiber cells, and their expression levels are simultaneously reduced with fiber cell maturation. Taken together, these data suggested that UAP56 is a novel regulator of HSF4 and might upregulate HSF4's downstream mRNA maturation and nuclear exportation.

Regulation of Sucrose Transporters and Phloem Loading in Response to Environmental Cues.

Suc transporters (SUTs) play a key role in the allocation and partitioning of photosynthetically fixed carbon in plants. While a function could be assigned to many members of the SUT family, almost no information is available on their regulation. Here, the transcriptional regulation of SUTs in response to various environmental stimuli in the leaves of five dicots (Arabidopsis [Arabidopsis thaliana], soybean [Glycine max], potato [Solanum tuberosum], tomato [Solanumlycopersicum], and poplar [Populus spp.]) and four monocots (maize [Zeamays], rice [Oryza sativa], wheat [Triticum aestivum], and barley [Hordeum vulgare]) was investigated. Extensive data on expression of SUTs in relation to changes of environmental conditions were obtained through a global analysis of 168 transcriptomics data sets. Results were validated by quantitative PCR measurements and extended by the measurement of photosynthesis rate and phloem sugar content to draw insight on the correlation of SUT expression and sugar export from leaves. For the apoplasmic phloem loaders, a clear difference in transcriptional regulation in response to different environmental stimuli was observed. The consistent patterns of SUT expression under abiotic stress indicates which types of SUTs are involved in the regulation of leaf sugar status and in stress signaling. Furthermore, it is shown that down-regulation of phloem loading is likely to be caused by transcriptional regulation of SUTs, while up-regulation depends on post-transcriptional regulation. In poplar, expression of PtaSUT4 was found to consistently respond to environmental stimuli, suggesting a significant role in the regulation of sugar export from leaves in this passive symplasmic phloem loader.

Comprehensive analysis of nucleocytoplasmic dynamics of mRNA in Drosophila cells

Eukaryotic mRNAs undergo a cycle of transcription, nuclear export, and degradation. A major challenge is to obtain a global, quantitative view of these processes. Here we measured the genome-wide nucleocytoplasmic dynamics of mRNA in Drosophila cells by metabolic labeling in combination with cellular fractionation. By mathematical modeling of these data we determined rates of transcription, export and cytoplasmic decay for 5420 genes. We characterized these kinetic rates and investigated links with mRNA features, RNA-binding proteins (RBPs) and chromatin states. We found prominent correlations between mRNA decay rate and transcript size, while nuclear export rates are linked to the size of the 3'UTR. Transcription, export and decay rates are each associated with distinct spectra of RBPs. Specific classes of genes, such as those encoding cytoplasmic ribosomal proteins, exhibit characteristic combinations of rate constants, suggesting modular control. Binding of splicing factors is associated with faster rates of export, and our data suggest coordinated regulation of nuclear export of specific functional classes of genes. Finally, correlations between rate constants suggest global coordination between the three processes. Our approach provides insights into the genome-wide nucleocytoplasmic kinetics of mRNA and should be generally applicable to other cell systems.

204 The cardiac hepcidin/ferroportin axis is essntial for cardiac iron homeostasis and function

BackgroundIron deficiency and chronic heart failure are two of the most common disorders worldwide. Recent evidence has demonstrated that they are linked. Moreover, clinical trials have demonstrated the benefits of...

Abstract 378: Red Blood Cells From Patients With Type 2 Diabetes Induce Endothelial Dysfunction Through Up-Regulation of Arginase I

We previously showed that increased arginase activity is a key mechanism for endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM) thereby arginase inhibition improves endothelial function. Recently, we demonstrated a crucial role of red blood cells (RBCs) in control of cardiac function via an arginase-dependent regulation of nitric oxide export from RBCs, suggesting a direct interaction of RBCs with cardiovascular function. Considering an increase in arginase activity in T2DM, we hypothesized that RBCs induce endothelial dysfunction in T2DM via up-regulated arginase I. Healthy rat aortas were incubated with RBCs from patients with T2DM (T2DM-RBCs) and age-matched healthy subjects (H-RBCs) for 18 h in the absence and presence of the arginase inhibition or scavenging of reactive oxygen/nitrogen species (ROS/RNS). Following the incubation, endothelium-dependent and -independent relaxations (EDR and EIR) were determined using wire myograph. Human internal mammary arteries (IMAs) obtained from non-diabetic patients who underwent cardiac surgery were also incubated with RBCs for functional evaluation. Arginase activity and protein expression were determined in RBCs. EDR was impaired in vessels incubated with T2DM-RBCs (Emax: 43.2±3.0% in aortas, n=8; 32.3±2.7% in IMAs, n=3) but not H-RBCs (Emax: 74.3±3.4% in aortas; 71.5±5.1% in IMAs) in comparison with buffer (Emax: 74.4±2.3% in aortas; 73.1±5.0% in IMAs; P<0.01 vs. T2DM-RBCs). EIR was not affected by T2DM-RBCs. The impairment in EDR in rat aortas was fully reversed by inhibition of arginase, ROS and RNS in RBCs. Arginase activity was significantly elevated in T2DM-RBCs. The increased arginase activity was attributed to arginase I, as there was increased arginase I expression in RBCs, whereas no arginase II expression was detected. Moreover, high glucose and RNS stimulation increased arginase activity in H-RBCs, while ROS/RNS scavenging decreased arginase activity in T2DM-RBCs. This study demonstrates a novel mechanism behind endothelial dysfunction that T2DM-RBCs induce endothelial dysfunction via ROS/RNS-dependent up-regulation of arginase I. Targeting arginase I in RBCs may serve as a novel therapeutic tool for treatment of endothelial dysfunction in T2DM.

Trinucleotide-repeat expanded and normal DMPK transcripts contain unusually long poly(A) tails despite differential nuclear residence

In yeast and higher eukaryotes nuclear retention of transcripts may serve in control over RNA decay, nucleocytoplasmic transport and premature cytoplasmic appearance of mRNAs. Hyperadenylation of RNA is known to be associated with nuclear retention, but the cause-consequence relationship between hyperadenylation and regulation of RNA nuclear export is still unclear. We compared polyadenylation status between normal and expanded DMPK transcripts in muscle cells and tissues derived from unaffected individuals and patients with myotonic dystrophy type 1 (DM1). DM1 is an autosomal dominant disorder caused by (CTG)n repeat expansion in the DMPK gene. DM1 etiology is characterized by an almost complete block of nuclear export of DMPK transcripts carrying a long (CUG)n repeat, including aberrant sequestration of RNA-binding proteins. We show here by use of cell fractionation, RNA size separation and analysis of poly(A) tail length that a considerable fraction of transcripts from the normal DMPK allele is also retained in the nucleus (~30%). They carry poly(A) tails with an unusually broad length distribution, ranging between a few dozen to >500 adenosine residues. Remarkably, expanded DMPK (CUG)n transcripts from the mutant allele, almost exclusively nuclear, carry equally long poly(A) tails. Our findings thus suggest that nuclear retention may be a common feature of regulation of DMPK RNA expression. The typical forced nuclear residence of expanded DMPK transcripts affects this regulation in tissues of DM1 patients, but not through hyperadenylation.

5-methylcytosine promotes mRNA export \u2014 NSUN2 as the methyltransferase and ALYREF as an m5C reader

5-methylcytosine (m5C) is a post-transcriptional RNA modification identified in both stable and highly abundant tRNAs and rRNAs, and in mRNAs. However, its regulatory role in mRNA metabolism is still largely unknown. Here, we reveal that m5C modification is enriched in CG-rich regions and in regions immediately downstream of translation initiation sites and has conserved, tissue-specific and dynamic features across mammalian transcriptomes. Moreover, m5C formation in mRNAs is mainly catalyzed by the RNA methyltransferase NSUN2, and m5C is specifically recognized by the mRNA export adaptor ALYREF as shown by in vitro and in vivo studies. NSUN2 modulates ALYREF's nuclear-cytoplasmic shuttling, RNA-binding affinity and associated mRNA export. Dysregulation of ALYREF-mediated mRNA export upon NSUN2 depletion could be restored by reconstitution of wild-type but not methyltransferase-defective NSUN2. Our study provides comprehensive m5C profiles of mammalian transcriptomes and suggests an essential role for m5C modification in mRNA export and post-transcriptional regulation.

SGK1 affects RAN/RANBP1/RANGAP1 via SP1 to play a critical role in pre-miRNA nuclear export: a new route of epigenomic regulation

The serum- and glucocorticoid-regulated kinase (SGK1) controls cell transformation and tumor progression. SGK1 affects mitotic stability by regulating the expression of RANBP1/RAN. Here, we demonstrate that SGK1 fluctuations indirectly modify the maturation of pre-miRNAs, by modulating the equilibrium of the RAN/RANBP1/RANGAP1 axis, the main regulator of nucleo-cytoplasmic transport. The levels of pre-miRNAs and mature miRNAs were assessed by qRT-PCR, in total extracts and after differential nuclear/cytoplasmic extraction. RANBP1 expression is the limiting step in the regulation of SGK1-SP1 dependent nuclear export. These results were validated in unrelated tumor models and primary human fibroblasts and corroborated in tumor-engrafted nude mice. The levels of pri-miRNAs, DROSHA, DICER and the compartmental distribution of XPO5 were documented. Experiments using RANGTP conformational antibodies confirmed that SGK1, through RANBP1, decreases the level of the GTP-bound state of RAN. This novel mechanism may play a role in the epigenomic regulation of cell physiology and fate.

Genome-wide mapping of infection-induced SINE RNAs reveals a role in selective mRNA export.

Short interspersed nuclear elements (SINEs) are retrotransposons evolutionarily derived from endogenous RNA Polymerase III RNAs. Though SINE elements have undergone exaptation into gene regulatory elements, how transcribed SINE RNA impacts transcriptional and post-transcriptional regulation is largely unknown. This is partly due to a lack of information regarding which of the loci have transcriptional potential. Here, we present an approach (short interspersed nuclear element sequencing, SINE-seq), which selectively profiles RNA Polymerase III-derived SINE RNA, thereby identifying transcriptionally active SINE loci. Applying SINE-seq to monitor murine B2 SINE expression during a gammaherpesvirus infection revealed transcription from 28 270 SINE loci, with ∼50% of active SINE elements residing within annotated RNA Polymerase II loci. Furthermore, B2 RNA can form intermolecular RNA–RNA interactions with complementary mRNAs, leading to nuclear retention of the targeted mRNA via a mechanism involving p54nrb. These findings illuminate a pathway for the selective regulation of mRNA export during stress via retrotransposon activation.

Temporal and spatial regulation of mRNA export: Single particle RNA‐imaging provides new tools and insights

The transport of messenger RNAs (mRNAs) from the nucleus to cytoplasm is an essential step in the gene expression program of all eukaryotes. Recent technological advances in the areas of RNA-labeling, microscopy, and sequencing are leading to novel insights about mRNA biogenesis and export. This includes quantitative single molecule imaging (SMI) of RNA molecules in live cells, which is providing knowledge of the spatial and temporal dynamics of the export process. As this information becomes available, it leads to new questions, the reinterpretation of previous findings, and revised models of mRNA export. In this review, we will briefly highlight some of these recent findings and discuss how live cell SMI approaches may be used to further our current understanding of mRNA export and gene expression.

Implementing International Experience in Promoting Agricultural Products to Foreign Markets: The Russian Export Strategy

Almost all countries in the world actively regulate both import and export of agricultural products, however this process is very conflictгфд because of acute contradictions on the market. They are associated with the changing conditions of production, increase of attention of the world community to the food securitysituation, change of the used resources efficiency level, competition enhancement. Both internal and external components of agricultural producers support are important for Russia. That means the regulation should be aimed at meeting the needs of the domestic market and at increasing competitiveness of Russian products abroad. The development of the Russian export strategy for agricultural products is currently very important. This problem is closely related to the general subject of the agricultural productiondevelopment, but it has an explicit specific character. Inthiscontextexperienceofforeigncountriesisinteresting. Almost all tools of export regulation existing in the world practice are used in the foreign practice of export regulation of agricultural raw materials and food. Stimulation measures prevail in regards to the coverage of commodity items, number of episodes involving the use of agricultural export regulationmeasures, effectiveness of impact to the national agricultural sector. Holistic strategies of agricultural export development are not a widespread phenomenon abroad at the present stage of the world economy development. Their existence is typical for countries with a high level of food self-sufficiency. Special programs where export component is a harmonically built-in element are now more widely spread. Export development programs of the developed countries include a range of measures to maintain the target income level of producers and to maintain procurement and consumer prices. Export policy of the developing countries has a subordinated importance and is considered as one of the levels to develop national agriculture through the use of advantages of international division of labor.

Metabolic model of central carbon and energy metabolisms of growing Arabidopsis thaliana in relation to sucrose translocation.

BackgroundSucrose translocation between plant tissues is crucial for growth, development and reproduction of plants. Systemic analysis of these metabolic and underlying regulatory processes allow a detailed understanding of carbon distribution within the plant and the formation of associated phenotypic traits. Sucrose translocation from ‘source’ tissues (e.g. mesophyll) to ‘sink’ tissues (e.g. root) is tightly bound to the proton gradient across the membranes. The plant sucrose transporters are grouped into efflux exporters (SWEET family) and proton-symport importers (SUC, STP families). To better understand regulation of sucrose export from source tissues and sucrose import into sink tissues, there is a need for a metabolic model that takes in account the tissue organisation of Arabidopsis thaliana with corresponding metabolic specificities of respective tissues in terms of sucrose and proton production/utilization. An ability of the model to operate under different light modes (‘light’ and ‘dark’) and correspondingly in different energy producing modes is particularly important in understanding regulatory modules.ResultsHere, we describe a multi-compartmental model consisting of a mesophyll cell with plastid and mitochondrion, a phloem cell, as well as a root cell with mitochondrion. In this model, the phloem was considered as a non-growing transport compartment, the mesophyll compartment was considered as both autotrophic (growing on CO2 under light) and heterotrophic (growing on starch in darkness), and the root was always considered as heterotrophic tissue dependent on sucrose supply from the mesophyll compartment. In total, the model includes 413 balanced compounds interconnected by 400 transformers. The structured metabolic model accounts for central carbon metabolism, photosynthesis, photorespiration, carbohydrate metabolism, energy and redox metabolisms, proton metabolism, biomass growth, nutrients uptake, proton gradient generation and sucrose translocation between tissues. Biochemical processes in the model were associated with gene-products (742 ORFs). Flux Balance Analysis (FBA) of the model resulted in balanced carbon, nitrogen, proton, energy and redox states under both light and dark conditions. The main H+-fluxes were reconstructed and their directions matched with proton-dependent sucrose translocation from ‘source’ to ‘sink’ under any light condition.ConclusionsThe model quantified the translocation of sucrose between plant tissues in association with an integral balance of protons, which in turn is defined by operational modes of the energy metabolism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12870-016-0868-3) contains supplementary material, which is available to authorized users.

Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress.

T cell egress from the thymus is essential for adaptive immunity and involves chemotaxis along a sphingosine-1-phosphate (S1P) gradient. Pericytes at the corticomedullary junction produce the S1P egress signal, whereas thymic parenchymal S1P levels are kept low through S1P lyase (SPL)-mediated metabolism. Although SPL is robustly expressed in thymic epithelial cells (TECs), in this study, we show that deleting SPL in CD11c+ dendritic cells (DCs), rather than TECs or other stromal cells, disrupts the S1P gradient, preventing egress. Adoptive transfer of peripheral wild-type DCs rescued the egress phenotype of DC-specific SPL knockout mice. These studies identify DCs as metabolic gatekeepers of thymic egress. Combined with their role as mediators of central tolerance, DCs are thus poised to provide homeostatic regulation of thymic export.

MicroRNAs target SRSF7 splicing factor to modulate the expression of osteopontin splice variants in renal cancer cells

SRSF7 is a SR splicing factor involved in the regulation of splicing and mRNA export of cancer-related genes. The mechanisms regulating the expression of SRSF7 are unknown.This study shows that SRSF7 expression in cancer cells is regulated by microRNAs: short, non-coding RNAs that bind to 3′UTR of target genes and downregulate their expression. We show that microRNAs miR-30a-5p and miR-181a-5p together with SRSF7 form regulatory feedback loop in which the expression of microRNAs is recurrently regulated by its target. Finally, we demonstrate that silencing of SRSF7 affects the expression of osteopontin splice variants and decreases proliferation rate of renal cancer cells.

Anks1a regulates COPII-mediated anterograde transport of receptor tyrosine kinases critical for tumorigenesis.

ErbB2 signalling, which is amplified by EphA2 binding, is an important therapeutic target for breast cancer. Despite the importance of the EphA2/ErbB2 complex in promoting breast tumorigenesis, the mechanism by which these receptor tyrosine kinases (RTKs) are exported from the endoplasmic reticulum (ER) remains poorly understood. Here we report that the PTB adaptor Anks1a is specifically localized to the ER on its own serine phosphorylation. Once there, Anks1a acts as an important regulator of COPII-mediated EphA2 ER export. The Anks1a ankyrin repeat domain binds EphA2 and causes it to accumulate at sites of ER exit. Simultaneously, the Anks1a PTB domain binds Sec23. This induces internalization of EphA2 via COPII vesicles, while Anks1a remains behind on the ER membrane. EphA2 also binds ErbB2 in the ER and seems to load ErbB2 into growing COPII carriers. Together, our study reveals a novel mechanism that regulates the loading of RTKs into COPII vesicles.

A reactivity-based probe of the intracellular labile ferrous iron pool.

Improved methods for studying intracellular reactive iron(II) are of significant interest for studies of iron metabolism and disease relevant changes in iron homeostasis. Here we describe a highly-selective reactivity-based probe in which Fenton-type reaction with intracellular labile iron(II) leads to unmasking of the aminonucleoside puromycin. Puromycin leaves a permanent and dose-dependent mark on treated cells that can be detected with high sensitivity and precision using the high-content, plate-based immunofluorescence assay described. Using this new probe and screening approach, we detected alteration of cellular labile iron(II) in response extracellular iron conditioning, overexpression of iron storage and/or export proteins, and post-translational regulation of iron export. Finally, we utilized this new tool to demonstrate the presence of augmented labile iron(II) pools in cancer cells as compared to non-tumorigenic cells.

Programming Effects of Infant Diet on Cholesterol/Bile Acid Synthesis and Absorption in Piglets

Unlike breast milk, infant milk formula contains little cholesterol, and requirements necessary for normal growth and development are met through increased endogenous cholesterol synthesis in the liver. Human studies looking at the long‐term metabolic implications of manipulating cholesterol homeostasis during infancy have reported lower circulating cholesterol and triglycerides in adults that were breast fed when compared those that received formula. To determine the molecular etiology of diet‐associated changes in early‐life cholesterol metabolism, we employed a neonatal piglet feeding model to investigate differences in cholesterol homeostasis between two infant diets (sow's milk and a cow's milk‐based formula). Male and female piglets (n=12) were breast fed and compared to piglets (n=12) receiving a commercially available milk‐based formula from postnatal day 2 to day 21. As expected, we observed a significant up‐regulation of liver transcripts associated with hepatic cholesterol synthesis, including 3‐hydroxy‐3‐methylglutaryl‐Co‐A synthase (HMGCS1) and reductase (HMGR) in formula fed piglets. Using a non‐targeted metabolomic approach in the liver, we identified 47 significant features that differed between breast fed and formula fed piglets. Pathway analysis identified taurine metabolism and bile acid metabolism among the top pathways elevated in formula fed piglets compared to those breast fed. Presently, we have confirmed increases in hepatic taurine (p=0.02), taurochenodeoxycholic acid (p=0.002) and glycoursodexoycholic acid, (p=0.002) and a decrease in taurocholic acid (p=0.01) in the formula fed group compared to breast fed piglets. Consistent with these data, in formula fed males and females we also observed a significant increase in cholesterol 7α‐hydroxylase (CYP7A1) mRNA and protein expression (p<0.05), indicating excessive bile acid production. In the liver farnesoid X receptor (FXR) regulation of bile acid synthesis and export were intact. We observed a significant decrease in CYP8B1 mRNA expression, with 2‐fold increases in mRNA expression of the bile acid export pump (BSEP) and multidrug resistance protein 2 (MDR2), p<0.05. In females, intestinal mRNA expression of the cholesterol pathway regulator fibroblast factor 19 (FGF 19) was reduced by 4‐fold in response to the formula diet (p<0.05), suggesting that loss of intestinal FGF19 signaling is responsible for the increase in CYP7A1 expression. In conclusion, formula feeding elicits profound metabolic programming effects on hepatic and intestinal regulation of cholesterol/bile acid metabolism in a neonatal piglet model of human infant nutrition.Support or Funding InformationThis work was funded by USDA‐ARS Project 6026‐5100‐010‐05S.

ORC interacts with THSC/TREX-2 and its subunits promote Nxf1 association with mRNP and mRNA export in Drosophila.

The origin recognition complex (ORC) of eukaryotes associates with the replication origins and initiates the pre-replication complex assembly. In the literature, there are several reports of interaction of ORC with different RNAs. Here, we demonstrate for the first time a direct interaction of ORC with the THSC/TREX-2 mRNA nuclear export complex. The THSC/TREX-2 was purified from the Drosophila embryonic extract and found to bind with a fraction of the ORC. This interaction occurred via several subunits and was essential for Drosophila viability. Also, ORC was associated with mRNP, which was facilitated by TREX-2. ORC subunits interacted with the Nxf1 receptor mediating the bulk mRNA export. The knockdown of Orc5 led to a drop in the Nxf1 association with mRNP, while Orc3 knockdown increased the level of mRNP-bound Nxf1. The knockdown of Orc5, Orc3 and several other ORC subunits led to an accumulation of mRNA in the nucleus, suggesting that ORC participates in the regulation of the mRNP export.

A Nuclear Attack on Traumatic Brain Injury: Sequestration of Cell Death in the Nucleus.

SummaryBackgroundExportin 1 (XPO1/CRM1) plays prominent roles in the regulation of nuclear protein export. Selective inhibitors of nuclear export (SINE) are small orally bioavailable molecules that serve as drug‐like inhibitors of XPO1, with potent anti‐cancer properties. Traumatic brain injury (TBI) presents with a secondary cell death characterized by neuroinflammation that is putatively regulated by nuclear receptors.Aims and ResultsHere, we report that the SINE compounds (KPT‐350 or KPT‐335) sequestered TBI‐induced neuroinflammation‐related proteins (NF‐kB, AKT, FOXP1) within the nucleus of cultured primary rat cortical neurons, which coincided with protection against TNF‐α (20 ng/mL)‐induced neurotoxicity as shown by at least 50% and 100% increments in preservation of cell viability and cellular enzymatic activity, respectively, compared to non‐treated neuronal cells (P's < 0.05). In parallel, using an in vivo controlled cortical impact (CCI) model of TBI, we demonstrate that adult Sprague‐Dawley rats treated post‐injury with SINE compounds exhibited significant reductions in TBI‐induced behavioral and histological deficits. Animals that received KPT‐350 orally starting at 2 h post‐TBI and once a day thereafter over the next 4 days exhibited significantly better motor coordination, and balance in the rotorod test and motor asymmetry test by 100–200% improvements, as early as 4 h after initial SINE compound injection that was sustained during subsequent KPT‐350 dosing, and throughout the 18‐day post‐TBI study period compared to vehicle treatment (P's < 0.05). Moreover, KPT‐350 reduced cortical core impact area and peri‐impact cell death compared to vehicle treatment (P's < 0.05).ConclusionsBoth in vitro and in vivo experiments revealed that KPT‐350 increased XPO1, AKT, and FOXP1 nuclear expression and relegated NF‐kB expression within the neuronal nuclei. Altogether, these findings advance the utility of SINE compounds to stop trafficking of cell death proteins within the nucleus as an efficacious treatment for TBI.