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ATP-binding cassette (ABC) transporters act mainly to transport compounds across cellular membranes and are important for diverse biological processes. However, their roles in pathogenesis have not been well-characterized in Fusarium graminearum. Sixty F. graminearum ABC protein genes were functionally characterized. Among them, FgArb1 regulates normal growth and importantly is essential for pathogenicity. Thus, the regulatory mechanisms of FgArb1 in pathogenicity were analyzed in this study. FgArb1 interacts with the mitogen-activated protein kinase (MAPK) FgSte7, and partially modulates plant penetration by regulating the phosphorylation of FgGpmk1 (the downstream kinase of FgSte7). The FgArb1 mutant exhibited dramatically reduced infective growth within wounded host tissues, likely resulting from its increased sensitivity to oxidative stresses, defective cell wall integrity and reduced deoxynivalenol (DON) production. FgArb1 also is important for the production of sexual and asexual spores that are important propagules for plant infection. In addition, FgArb1 is involved in the regulation of protein biosynthesis through impeding nuclear export of small ribosomal subunit. Finally, acetylation modification at sites K28, K65, K341 and K525 in FgArb1 is required for its biological functions. Taken together, results of this study provide a novel insight into functions of the ABC transporter in fungal pathogenesis.

High cholesterol is a major risk factor for cardiovascular disease 1 . Currently, no drug lowers cholesterol through directly promoting cholesterol excretion. Human genetic studies have identified that the loss-of-function Asialoglycoprotein receptor 1 ( ASGR1 ) variants associate with low cholesterol and a reduced risk of cardiovascular disease 2 . ASGR1 is exclusively expressed in liver and mediates internalization and lysosomal degradation of blood asialoglycoproteins 3 . The mechanism by which ASGR1 affects cholesterol metabolism is unknown. Here, we find that Asgr1 deficiency decreases lipid levels in serum and liver by stabilizing LXRα. LXRα upregulates ABCA1 and ABCG5/G8, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and faeces 4 , respectively. ASGR1 deficiency blocks endocytosis and lysosomal degradation of glycoproteins, reduces amino-acid levels in lysosomes, and thereby inhibits mTORC1 and activates AMPK. On one hand, AMPK increases LXRα by decreasing its ubiquitin ligases BRCA1/BARD1. On the other hand, AMPK suppresses SREBP1 that controls lipogenesis. Anti-ASGR1 neutralizing antibody lowers lipid levels by increasing cholesterol excretion, and shows synergistic beneficial effects with atorvastatin or ezetimibe, two widely used hypocholesterolaemic drugs. In summary, this study demonstrates that targeting ASGR1 upregulates LXRα, ABCA1 and ABCG5/G8, inhibits SREBP1 and lipogenesis, and therefore promotes cholesterol excretion and decreases lipid levels. Inhibiting the asialoglycoprotein receptor ASGR1 increases cholesterol excretion to the bile and then faeces, providing a unique way to lower cholesterol, and therefore providing a safe and effective way to treat cardiovascular disease.

Colorectal cancer (CRC) is one of the most prevalent and deadly cancers worldwide, with late-stage diagnosis often associated with poor prognosis. The natural compound narirutin has shown various biological activities, including anti-inflammatory and anti-cancer effects, indicating its potential clinical application. This study aims to identify the key targets and potential mechanisms of narirutin treatment in colorectal cancer (CRC) through comprehensive bioinformatics analysis and machine learning methods, emphasizing its importance as a potential therapeutic agent. We utilized SwissTargetPrediction to identify 23 target genes of narirutin, followed by differential expression analysis of 3,338 genes from the TCGA-COAD dataset. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on the intersecting genes, and machine learning techniques to identify hub genes. Additionally, we conducted molecular docking studies and immune infiltration analyses. Our findings revealed that narirutin targets key genes, including ABCC1, ABCG2, CA12, EPHX2, and PTGS1, which are significantly involved in CRC progression. Enrichment analyses indicated that these genes participate in crucial pathways related to drug metabolism and immune response. Molecular docking results demonstrated favorable binding affinities between narirutin and its target proteins. Furthermore, immune cell infiltration analysis showed significant differences in various immune cell types between CRC and control groups, suggesting their role in tumor microenvironment dynamics. Narirutin may play a vital role in CRC treatment by modulating key genes and pathways, underscoring its potential as a therapeutic agent. Future studies should explore its clinical applicability and mechanisms further.

Fibroblasts from patients with Tangier disease carrying ATP-binding cassette A1 (ABCA1) loss-of-function mutations are characterized by cardiolipin accumulation, a mitochondrial-specific phospholipid. Suppression of ABCA1 expression occurs in glomeruli from patients with diabetic kidney disease (DKD) and in human podocytes exposed to DKD sera collected prior to the development of DKD. We demonstrated that siRNA ABCA1 knockdown in podocytes led to reduced oxygen consumption capabilities associated with alterations in the oxidative phosphorylation (OXPHOS) complexes and with cardiolipin accumulation. Podocyte-specific deletion of Abca1 (Abca1fl/fl) rendered mice susceptible to DKD, and pharmacological induction of ABCA1 improved established DKD. This was not mediated by free cholesterol, as genetic deletion of sterol-o-acyltransferase-1 (SOAT1) in Abca1fl/fl mice was sufficient to cause free cholesterol accumulation but did not cause glomerular injury. Instead, cardiolipin mediates ABCA1-dependent susceptibility to podocyte injury, as inhibition of cardiolipin peroxidation with elamipretide improved DKD in vivo and prevented ABCA1-dependent podocyte injury in vitro and in vivo. Collectively, we describe a pathway definitively linking ABCA1 deficiency to cardiolipin-driven mitochondrial dysfunction. We demonstrated that this pathway is relevant to DKD and that ABCA1 inducers or inhibitors of cardiolipin peroxidation may each represent therapeutic strategies for the treatment of established DKD.

Streptococcus suis is a significant pathogen in pigs and a newly emerging zoonotic agent in humans. The presence of multiple serotypes and strains with diversified sequence types in pig herds highlights the need for the identification of broadly cross-reactive universal vaccine antigen targets, capable of providing cross-protection against S. suis infection. Subunit vaccines based on the conserved proteins shared between different S. suis serotypes are potential candidates for such a universally protective vaccine. In the present study, phosphate ABC transporter ATP-binding protein PstB (PstB), an immunogenic protein of the S. suis bacterium, was expressed and purified, and then subjected to cross-protection evaluation in mice. The PstB protein showed nearly 100% amino acid similarity across a panel of 31 S. suis isolates representing different serotypes, which were collected from different countries. A recombinant PstB (rPstB) protein (S. suis serotype 2) was recognized by rabbit sera specific to this serotype, and induced high levels of IFN-γ and IL-4 in mice immunized with the recombinant protein. These cytokines are considered important for protection against S. suis infection. Immunization of mice with rPstB resulted in an 87.5% protection against challenge with S. suis serotype 2 and 9 strains, suggesting a high level of cross-protection for S. suis serotypes 2 and 9. A lower protection rate (62.5%) was observed in mice challenged with the S. suis serotype 7 strain. These data demonstrate that PstB is a promising target antigen for development as a component of a universal subunit vaccine against multiple S. suis serotypes.

Background PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment. Methods The effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP. Results By inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb , the ATP-binding cassette transporters P-gp/ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently. Conclusions The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.

Production of high density lipoprotein (HDL) requires ATP-binding cassette transporter A1 (ABCA1) to drive phospholipid (PL) from the plasma membrane into extracellular apolipoprotein A-I. Here, we use simulations to show that domains of ABCA1 within the plasma membrane remove PL from the membrane’s outer leaflet. In our simulations, after the lipid diffuses into the interior of ABCA1’s outward-open cavity, PL extracted by the gateway passes through a ring-shaped domain, the annulus orifice, which forms the base of an elongated hydrophobic tunnel in the transporter’s extracellular domain. Engineered mutations in the gateway and annulus strongly inhibit lipid export by ABCA1 without affecting cell-surface expression levels. Our finding that ABCA1 extracts lipid from the outer face of the plasma membrane and forces it through its gateway and annulus into an elongated hydrophobic tunnel contrasts with the alternating access model, which proposes that ABCA1 flops PL substrate from the inner leaflet to the outer leaflet of the membrane. Consistent with our model, ABCA1 lacks the charged amino acid residues in the transmembrane domain found in the floppase members of the ABC transporter family. ATP-binding cassette transporter A1 (ABCA1) drives phospholipid (PL) from the plasma membrane into extracellular apolipoprotein A-I, for the production of high density lipoprotein (HDL). Here, the authors use simulations to assess the mechanism of ABCA1 function and show that ABCA1 extracts lipid from the outer face of the plasma membrane.

Sterol regulatory element-binding protein 2 (SREBP-2) transcription factor has been identified as a key protein in cholesterol metabolism through the transactivation of the LDL receptor and cholesterol biosynthesis genes. Here, we generated mice lacking microRNA (miR)-33, encoded by an intron of the Srebp2, and showed that miR-33 repressed the expression of ATP-binding cassette transporter A 1 (ABCA 1) protein, a key regulator of HDL synthesis by mediating cholesterol efflux from cells to apolipoprotein A (apoA)-I. In fact, peritoneal macrophages derived from miR-33—deficient mice showed a marked increase in ABCA 1 levels and higher apoA-I—dependent cholesterol efflux than those from WT mice. ABCA 1 protein levels in liver were also higher in miR-33—deficient mice than in WT mice. Moreover, miR-33—deficient mice had significantly higher serum HDL cholesterol levels than WT mice. These data establish a critical role for miR-33 in the regulation of ABCA 1 expression and HDL biogenesis in vivo.

Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70% 1 . The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants 2 . Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2 , SORL1 and ABCA7 , we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10 . Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD. Multistage gene burden analysis in exome sequencing data from 32,558 individuals identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease.

ATP-binding cassette (ABC) transporters are molecular machines involved in diverse physiological processes, including antigen processing by TAP, a key component of adaptive immunity. TAP and its bacterial homolog TmrAB use ATP to translocate peptides across membranes, yet the precise mechanism linking ATP binding to substrate movement remains unclear. Here, we employ a single-molecule FRET sensor to visualize single translocation events by individual ABC transporters and thereby overcome the limitations of ensemble averaging. This approach reveals that substrate transport is driven by a conformational switch from the inward- to the outward-facing state. Using a slow-turnover TmrAB variant, we demonstrate that ATP binding alone, even in the absence of Mg 2+ , is sufficient to drive a single round of peptide translocation. Cryo-EM structures of wild-type and slow-turnover TmrAB show that ATP binding induces the outward-facing conformation even without Mg 2+ . In wild-type TmrAB, this conformational transition supports a single translocation event, whereas Mg 2+ -dependent ATP hydrolysis is required to reset the transporter. These findings establish a direct mechanistic link between ATP binding and substrate translocation at single-molecule resolution and provide insight into the catalytic cycle of ABC transporters. ATP-binding cassette transporters use ATP to move peptides across membranes, but how ATP binding drives transport is unclear. Here, authors visualize single transport events and show that ATP binding alone triggers peptide translocation via a conformational switch.