Ask about this productRelated genes to: SLC39A9 Blocking Peptide
- Gene:
- SLC39A9 NIH gene
- Name:
- solute carrier family 39 member 9
- Previous symbol:
- -
- Synonyms:
- FLJ11274
- Chromosome:
- 14q24.1
- Locus Type:
- gene with protein product
- Date approved:
- 2003-10-08
- Date modifiied:
- 2015-12-08
Related products to: SLC39A9 Blocking Peptide
Related articles to: SLC39A9 Blocking Peptide
- Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by elevated total bile acid (TBA) levels, leading to adverse maternal and fetal outcomes. While genetic factors contribute to ICP and bile acid metabolism, the underlying mechanisms remain incompletely understood, particularly in East Asian populations. We conducted a genome-wide association study (GWAS) in 13,357 pregnant women from a Chinese cohort to investigate genetic determinants of TBA levels and ICP. Meta-analysis was performed by combining our data with the Shenzhen cohort. Post-GWAS analyses included pathway enrichment, integrative analysis with liver single-cell RNA sequencing (scRNA-seq) data, and Mendelian randomization (MR). We identified genome-wide significant associations at CYP7A1 (rs4738680, p = 1.08 × 10) and SLC39A9 (rs17107007, p = 3.46 × 10) for TBA, and at SLC39A9 (rs17107007, p = 3.34 × 10) for ICP. Pathway analysis highlighted bile acid synthesis and metabolism pathways for TBA and immune-related pathways for ICP. Integrative scRNA-seq analysis revealed enrichment of TBA-associated genes in hepatocytes and ICP-associated genes in neutrophils. MR analysis suggested a potential causal effect of estrone on TBA levels. Our findings provide novel insights into the genetic architecture of TBA and ICP, emphasizing the roles of bile acid metabolism in hepatocytes and immune dysregulation in ICP pathogenesis. The identified genetic loci and pathways may inform future research on risk prediction and targeted therapies for ICP. - Source: PubMed
Zhang XinyiLi JunweiZhu HuanhuanLi LinxuanWang YuYang MengWang LinLan XianmeiWang YingyingLin YingZeng JingyuLiu PanhongZhou AifenXiao HanJin Xin - Synucleinopathies are characterized by the accumulation and propagation of α-synuclein (α-syn) aggregates throughout the brain, leading to neuronal dysfunction and death. In this study, we used an unbiased FACS-based genome-wide CRISPR/Cas9 knockout screening to identify genes that regulate the entry and accumulation of α-syn preformed fibrils (PFFs) in cells. We identified key genes and pathways specifically implicated in α-syn PFFs intracellular accumulation, including heparan sulfate proteoglycans (HSPG) biosynthesis and Golgi trafficking. All confirmed hits affected heparan sulfate (HS), a post-translational modification known to act as a receptor for proteinaceous aggregates including α-syn and tau. Intriguingly, deletion of SLC39A9 and C3orf58 genes, encoding respectively a Golgi-localized exporter of Zn, and the Golgi-localized putative kinase DIPK2A, specifically impaired the uptake of α-syn PFFs, by preventing the binding of PFFs to the cell surface. Mass spectrometry-based analysis of HS chains in SLC39A9 and C3orf58 cells indicated major defects in HS homeostasis. Additionally, Golgi accumulation of NDST1, a prime HSPG biosynthetic enzyme, was detected in C3orf58 cells. Interestingly, C3orf58 human iPSC-derived microglia and dopaminergic neurons exhibited a strong reduction in their ability to internalize α-syn PFFs. Altogether, our data identifies new modulators of HSPGs that regulate α-syn PFFs cell surface binding and uptake. - Source: PubMed
Publication date: 2025/10/06
Vanderperre BenoîtMuraleedharan AmithaDorion Marie-FranceLarroquette FrédériqueDel Cid Pellitero EstherRajakulendran NishaniChen Carol X-QLarivière RoxanneMichaud-Tardif CharlotteGoiran ThomasChidiac RonyLipuma DamienMacLeod GrahamThomas RhalenaWang ZhangjieReintsch Wolfgang ELuo WenShlaifer IrinaZhang FumingXia KeSteinhart ZacharyLinhardt Robert JTrempe Jean-FrançoisLiu JianDurcan Thomas MAngers StephaneFon Edward A - Over the past few decades, a significant change globally in sugar intake has coincided with a rising incidence of male infertility, which is now a major public health concern. Diets rich in fructose have been implicated in both male infertility and increased susceptibility to metabolic disorders, such as obesity, diabetes, and related heart problems. While fructose is known to be present in seminal fluid and crucial for sperm motility, the precise role of fructose in testicular function remains largely unknown. GLUT5 is an exclusive fructose transporter essential for dietary fructose uptake in the intestine. It is also expressed mainly in germ and Leydig cells. We recently revealed that disrupting the Glut5 gene in male mice impairs spermatogenesis and steroidogenesis. However, its specific role within Leydig cells remains unexplored. Therefore, we investigated its role by inhibiting GLUT5 in a murine Leydig cell line (mLTC-1) using a specific inhibitor of GLUT5, MSNBA, combined with a multi-omics approach. Exposing mLTC-1 cells to MSNBA reduced the intracellular fructose content, limited cell proliferation, and enhanced progesterone and androgens production (Δ4-androstenedione and testosterone). The latter was associated with the upregulation of two genes and proteins involved in steroidogenesis, such as Hsd3b and steroidogenic acute regulatory protein (StAR). GLUT5 inhibition in mLTC-1 cells also modified lipid and carbohydrate metabolism. Lipidomic analysis showed decreased cholesterol esters and a shift in the ratio of polyunsaturated fatty acids (PUFAs) to monounsaturated fatty acids (MUFAs). These lipid changes correlated with alterations in the expression of mRNA-encoding enzymes involved in lipogenesis, such as ELOVL6. Metabolomics analysis showed a reduction in most glycolysis metabolites, except for pyruvate and lactate. However, pyruvate could conserve its level by a production through an amino acid pathway using the higher branched-chain amino acid content. Nevertheless, the activity of mitochondria measured by seahorse was not altered. The transcriptomic analysis performed by BRB-seq approach revealed an upregulation of several androgen-sensitive genes, such as Akap5, Slc39a9, an androgen receptor or lactate dehydrogenase A (Ldha), which produces lactate, and downregulation of several genes associated with the insulin pathway such as Tsc2 or the hexokinase Hkdc1. In conclusion, GLUT5 supported fructose intake in the murine Leydig cell line mLTC-1, leading to a reduction in cell proliferation. The consequences of inhibition of GLUT5 led to an increase in fatty acids cell content, a perturbation in glycolysis and amino-acid metabolism but an enhanced androgen production. Since androgens regulate spermatogenesis, hyperandrogenism induced by a lower fructose content in Leydig cells may be a primary cause leading to the disruption of sperm production and quality, as well as sexual behavior, as described in the GLUT5 KO mouse model. - Source: PubMed
Publication date: 2025/09/12
Kallianioti AikateriniBourdon GuillaumeChevaleyre ClairePéchoux ChristineRamé ChristelleBourgeais JérômeHérault OlivierGeoffre NancyDarde ThomasPlotton IngridDouard VéroniqueDupont JoëlleFroment Pascal - Anti-PD1 therapies are primarily thought to rely on functional T cell responses; yet tumors with limited T cell infiltration can still benefit, suggesting alternative mechanisms contribute to therapeutic efficacy. Indeed, we found that myeloid-rich, T cell-poor tumor models respond to anti-Pd1, and this is dependent on a cancer cell-macrophage crosstalk mediated by cancer cell expression. Mechanistically, we found that cancer cells with decreased expression (C ), which occurs in ∼50% of all human cancers, reorganize zinc compartmentalization by upregulating the zinc importer Slc39a9 at the plasma membrane. Increased cancer cell plasma membrane Slc39a9 leads to intracellular zinc accumulation in cancer cells and depletion of zinc in the tumor microenvironment (TME), resulting in zinc-starved tumor-associated macrophages (TAMs) with reduced phagocytic activity. Restoring zinc availability in TAMs-via dietary supplementation or Slc39a9 knockdown in cancer cells-reprograms TAMs to a pro-phagocytic state and sensitizes tumors to anti-Pd1 therapy. Remarkably, Slc39a9 knockdown tumors respond to anti-Pd1 in Rag1 mice, and co-injection of zinc-replete macrophages is sufficient to drive an anti-Pd1 response in immunodeficient mice, demonstrating the T cell-independent nature of this response. Clinically, TAMs from cancer patients show reduced zinc and phagocytosis gene signatures. Moreover, patients with lower circulating zinc levels have significantly worse time-to-event outcomes than those with higher levels. Together, these findings uncover a previously unrecognized mechanism by which cancer cells outcompete TAMs for zinc, impairing their function and limiting anti-Pd1 efficacy. They also provide evidence that macrophages alone, without T cells, can enhance anti-PD1 response through zinc-mediated reprogramming of phagocytosis. - Source: PubMed
Publication date: 2025/08/05
Buj RaquelCole Aidan RDanielson JeffXu JimmyHurd DrewKishore AkashKedziora Katarzyna MChen JieYang BaixueBarras DavidUboveja ApoorvaAmalric AmandineApiz Saab Juan JWickramasinghe JayamannaTangudu Naveen KumarLevasseur EvanWang HuiMinasyan AspramDadey Rebekah ESharrow Allison CKunning SherylVendetti Frank PRivadeneira Dayana BBakkenist Christopher JBruno Tullia CDelgoffe Greg MHempel NadineSnyder Nathaniel WBao RiyueSoloff Adam CKirk-Wood John MDangaj Laniti DenardaKossenkov Andrew VMuir AlexanderDas JishnuDavar DiwakarMesaros ClementinaAird Katherine M - Hidradenitis suppurativa (HS) is a chronic skin condition that primarily affects areas with dense hair follicles and apocrine sweat glands, such as the underarms, groin, buttocks, and lower breasts. Intense pain and discomfort in HS have been commonly noted, primarily due to the lesions' effects on nearby tissues. Pain is a factor that can influence DNA methylation patterns, though its exact role in HS is not fully understood. We aim to identify molecular markers of chronic pain in HS patients. We performed DNA methylome of peripheral blood DNA derived from a group of 24 patients with HS and 24 healthy controls, using Illumina methylation array chips. We identified 253 significantly differentially methylated CpG sites across 253 distinct genes regulating pain sensitization in HS, including 224 hypomethylated and 29 hypermethylated sites. Several genes with pleiotropic roles include transporters (, , ), wound healing (, , ), ion channel regulators (, ), oxidative stress mediators (, , ), cytochromes (, ), cytokines (, ), telomere regulators (, , ), circadian rhythm (, , ), ultradian rhythms (, , ), hormonal regulation (, , ), and the serotonin system (, , , , ). They also play roles in glucose metabolism (, , ) and obesity (, , ). Gene ontology and pathway enrichment analysis identified 43 pathways, including calcium signaling, cocaine addiction, and nicotine addiction. This study identified multiple differentially methylated genes involved in chronic pain in HS, which may serve as biomarkers and therapeutic targets. Understanding their epigenetic regulation is crucial for personalized pain management and could enhance the identification of high-risk patients, leading to better preventative therapies and improved maternal and neonatal outcomes. - Source: PubMed
Publication date: 2025/01/25
Radhakrishna UppalaKuracha Murali RHamzavi IltefatSaiyed NaziaPrajapati JigneshRawal Rakesh MUppala Lavanya VDamiani GiovanniRatnamala UppalaNath Swapan K