Biochemical Journal最新文献_第10页

Retraction: Mechanism of short-term ERK activation by electromagnetic fields at mobile phone frequencies. 撤回：手机频率电磁场短期激活ERK的机制

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-10-02 DOI: 10.1042/bj20061653_ret

引用次数: 0

Lipoprotein(a) and cardiovascular disease. 脂蛋白（a）与心血管疾病。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-10-02 DOI: 10.1042/BCJ20240037

Michael B Boffa, Marlys L Koschinsky

引用次数: 0

Novel phosphatidylinositol flippases contribute to phosphoinositide homeostasis in the plasma membrane. 新型磷脂酰肌醇翻转酶有助于质膜中磷脂酰肌醇的平衡。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-09-18 DOI: 10.1042/BCJ20240223

Yumeka Muranaka, Ryo Shigetomi, Yugo Iwasaki, Asuka Hamamoto, Kazuhisa Nakayama, Hiroyuki Takatsu, Hye-Won Shin

{"title":"Novel phosphatidylinositol flippases contribute to phosphoinositide homeostasis in the plasma membrane.","authors":"Yumeka Muranaka, Ryo Shigetomi, Yugo Iwasaki, Asuka Hamamoto, Kazuhisa Nakayama, Hiroyuki Takatsu, Hye-Won Shin","doi":"10.1042/BCJ20240223","DOIUrl":"10.1042/BCJ20240223","url":null,"abstract":"Phosphatidylinositol is a precursor of various phosphoinositides, which play crucial roles in intracellular signaling and membrane dynamics and have impact on diverse aspects of cell physiology. Phosphoinositide synthesis and turnover occur in the cytoplasmic leaflet of the organellar and plasma membranes. P4-ATPases (lipid flippases) are responsible for translocating membrane lipids from the exoplasmic (luminal) to the cytoplasmic leaflet, thereby regulating membrane asymmetry. However, the mechanism underlying phosphatidylinositol translocation across cellular membranes remains elusive. Here, we discovered that the phosphatidylcholine flippases ATP8B1, ATP8B2, and ATP10A can also translocate phosphatidylinositol at the plasma membrane. To explore the function of these phosphatidylinositol flippases, we used cells depleted of CDC50A, a protein necessary for P4-ATPase function and ATP8B1 and ATP8B2, which express in HeLa cells. Upon activation of the Gq-coupled receptor, depletion of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] was accelerated in CDC50A knockout (KO) and ATP8B1/8B2 double KO cells compared with control cells, suggesting a decrease in PtdIns(4,5)P2 levels within the plasma membrane of the KO cells upon stimulation. These findings highlight the important role of P4-ATPases in maintaining phosphoinositide homeostasis and suggest a mechanism for asymmetry of phosphatidylinositol in the cytoplasmic leaflet of the plasma membrane.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"481 18","pages":"1187-1202"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation. CARD14 信号体的形成与其内表皮迁移和 mTORC1 诱导的角膜细胞增殖有关。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-09-18 DOI: 10.1042/BCJ20240058

Paul A O'Sullivan, Aigerim Aidarova, Inna S Afonina, Joan Manils, Teresa L M Thurston, Rachael Instrell, Michael Howell, Stefan Boeing, Sashini Ranawana, Melanie B Herpels, Riwia Chetian, Matilda Bassa, Helen Flynn, David Frith, Ambrosius P Snijders, Ashleigh Howes, Rudi Beyaert, Anne M Bowcock, Steven C Ley

{"title":"CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation.","authors":"Paul A O'Sullivan, Aigerim Aidarova, Inna S Afonina, Joan Manils, Teresa L M Thurston, Rachael Instrell, Michael Howell, Stefan Boeing, Sashini Ranawana, Melanie B Herpels, Riwia Chetian, Matilda Bassa, Helen Flynn, David Frith, Ambrosius P Snijders, Ashleigh Howes, Rudi Beyaert, Anne M Bowcock, Steven C Ley","doi":"10.1042/BCJ20240058","DOIUrl":"10.1042/BCJ20240058","url":null,"abstract":"Rare mutations in CARD14 promote psoriasis by inducing CARD14-BCL10-MALT1 complexes that activate NF-κB and MAP kinases. Here, the downstream signalling mechanism of the highly penetrant CARD14E138A alteration is described. In addition to BCL10 and MALT1, CARD14E138A associated with several proteins important in innate immune signalling. Interactions with M1-specific ubiquitin E3 ligase HOIP, and K63-specific ubiquitin E3 ligase TRAF6 promoted BCL10 ubiquitination and were essential for NF-κB and MAP kinase activation. In contrast, the ubiquitin binding proteins A20 and ABIN1, both genetically associated with psoriasis development, negatively regulated signalling by inducing CARD14E138A turnover. CARD14E138A localized to early endosomes and was associated with the AP2 adaptor complex. AP2 function was required for CARD14E138A activation of mTOR complex 1 (mTORC1), which stimulated keratinocyte metabolism, but not for NF-κB nor MAP kinase activation. Furthermore, rapamycin ameliorated CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice, suggesting that blocking mTORC1 may be therapeutically beneficial in CARD14-dependent psoriasis.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1143-1171"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pregnane X receptor inhibits the transdifferentiation of hepatic stellate cells by down-regulating periostin expression. 孕烷 X 受体通过下调骨膜增生蛋白的表达抑制肝星状细胞的转分化。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-09-18 DOI: 10.1042/BCJ20240172

Takumi Sato, Ryota Shizu, Ryonosuke Baba, Akira Ooka, Takuomi Hosaka, Yuichiro Kanno, Kouichi Yoshinari

{"title":"Pregnane X receptor inhibits the transdifferentiation of hepatic stellate cells by down-regulating periostin expression.","authors":"Takumi Sato, Ryota Shizu, Ryonosuke Baba, Akira Ooka, Takuomi Hosaka, Yuichiro Kanno, Kouichi Yoshinari","doi":"10.1042/BCJ20240172","DOIUrl":"10.1042/BCJ20240172","url":null,"abstract":"Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor that plays a key role in drug metabolism. Recently, PXR was found to attenuate the development of liver cancer by suppressing epithelial-mesenchymal transition (EMT) in liver cancer cells in a mouse model of two-stage chemical carcinogenesis. To elucidate the role of PXR in the EMT of liver cancer cells, we focused on its role in hepatic stellate cells (HSCs), which are components of the tumor microenvironment in hepatocellular carcinoma (HCC). Human HSC-derived LX-2 cells stably expressed destabilization domain (DD)-fused human PXR (hPXR-LX2 cells). Human HCC-derived HepG2 cells were transfected with the EMT marker VIM promoter-regulated reporter plasmid and co-cultured with hPXR-LX2 cells or treated with hPXR-LX2-derived conditioned medium (CM). Co-culture or CM treatment increased reporter activity in HepG2 cells. This induction was attenuated upon PXR activation in hPXR-LX2 cells by treatment with the DD-stabilizing chemical Shield-1 and the human PXR ligand rifampicin. PXR activation in hPXR-LX2 cells exhibited inhibition of TGF-β1-induced transdifferentiation, supported by observations of morphological changes and protein or mRNA levels of the transdifferentiation markers COL1A1 and FN1. PXR activation in hPXR-LX2 cells also attenuated the mRNA levels of the key transdifferentiation factor, POSTN. Treatment of hPXR-LX2 cells with recombinant POSTN restored the PXR-mediated suppression of transdifferentiation. Reporter assays with the POSTN promoter showed that PXR inhibited the NF-κB-mediated transcription of POSTN. Consequently, PXR activation in HSCs is expected to inhibit transdifferentiation by down-regulating POSTN expression, thereby suppressing EMT of liver cancer cells.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1173-1186"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Using a cellulose-complementary oligosaccharide as a tool to probe exposed cellulosic surfaces in cotton fibres and growing plant cell walls. 以纤维素互补寡糖为工具，探测棉纤维和生长植物细胞壁中暴露的纤维素表面。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-09-18 DOI: 10.1042/BCJ20240296

Mahnoor Imran, Lenka Franková, Uzma Qaisar, Stephen C Fry

{"title":"Using a cellulose-complementary oligosaccharide as a tool to probe exposed cellulosic surfaces in cotton fibres and growing plant cell walls.","authors":"Mahnoor Imran, Lenka Franková, Uzma Qaisar, Stephen C Fry","doi":"10.1042/BCJ20240296","DOIUrl":"10.1042/BCJ20240296","url":null,"abstract":"Cellulosic microfibrils in plant cell walls are largely ensheathed and probably tethered by hydrogen-bonded hemicelluloses. Ensheathing may vary developmentally as hemicelluloses are peeled to enable cell expansion. We characterised a simple method to quantify ensheathed versus naked cellulosic surfaces based on the ability to adsorb a radiolabelled 'cellulose-complementary oligosaccharide', [3H]cellopentaitol. Filter-paper (cellulose) adsorbed 40% and >80% of aqueous 5 nM [3H]cellopentaitol within ∼1 and ∼20 h respectively. When [3H]cellopentaitol was rapidly dried onto filter-paper, ∼50% of it was desorbable by water, whereas after ∼1 day annealing in aqueous medium the adsorption became too strong to be reversible in water. 'Strongly' adsorbed [3H]cellopentaitol was, however, ∼98% desorbed by 6 M NaOH, ∼50% by 0.2 M cellobiose, and ∼30% by 8 M urea, indicating a role for hydrogen-bonding reinforced by complementarity of shape. Gradual adsorption was promoted by kosmotropes (1.4 M Na2SO4 or 30% methanol), and inhibited by chaotropes (8 M urea), supporting a role for hydrogen-bonding. [3H]Cellopentaitol adsorption was strongly competed by non-radioactive cello-oligosaccharides (Cell2-6), the IC50 (half-inhibitory concentration) being highly size-dependent: Cell2, ∼70 mM; Cell3, ∼7 mM; and Cell4-6, ∼0.05 mM. Malto-oligosaccharides (400 mM) had no effect, confirming the role of complementarity. The quantity of adsorbed [3H]cellopentaitol was proportional to mass of cellulose. Of seven cottons tested, wild-type Gossypium arboreum fibres were least capable of adsorbing [3H]cellopentaitol, indicating ensheathment of their microfibrillar surfaces, confirmed by their resistance to cellulase digestion, and potentially attributable to a high glucuronoarabinoxylan content. In conclusion, [3H]cellopentaitol adsorption is a simple, sensitive and quantitative way of titrating 'naked' cellulose surfaces.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1221-1240"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The pro-drug C13 activates AMPK by two distinct mechanisms. 原药 C13 通过两种不同的机制激活 AMPK。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-09-18 DOI: 10.1042/BCJ20240425

Jordana B Freemantle, Dinesh Shah, Dylan M Lynch, Alessio Ciulli, Harinder S Hundal, D Grahame Hardie

{"title":"The pro-drug C13 activates AMPK by two distinct mechanisms.","authors":"Jordana B Freemantle, Dinesh Shah, Dylan M Lynch, Alessio Ciulli, Harinder S Hundal, D Grahame Hardie","doi":"10.1042/BCJ20240425","DOIUrl":"10.1042/BCJ20240425","url":null,"abstract":"The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is expressed in almost all eukaryotic cells. In the canonical activation mechanism, it is activated by increases in AMP:ATP and ADP:ATP ratios that signify declining cellular energy status. Once activated, AMPK phosphorylates numerous targets that promote catabolic pathways generating ATP, while inhibiting anabolic and other processes that consume ATP, thus acting to restore energy homeostasis. Pharmacological agents that activate AMPK have been useful in identifying downstream targets and have potential as drugs for treatment of metabolic disorders such as Type 2 diabetes and non-alcoholic fatty liver disease. One such agent is C13, a pro-drug with a phosphonate bis(isobutyryloxymethyl) ester moiety, with the isobutyryloxymethyl groups increasing membrane permeability. Following cellular uptake, C13 is cleaved to release C2, an AMP analogue and potent AMPK activator that is specific for complexes containing the α1 (but not the α2) catalytic subunit isoform. This has previously been assumed to be the sole mechanism by which C13 activates AMPK, with potential roles for the isobutyryloxymethyl groups being ignored. We now report that, following cleavage from C13, these protective groups are metabolized to formaldehyde, an agent that inhibits mitochondrial function and increases cellular AMP:ATP ratios, thus providing additional AMPK activation by the canonical mechanism.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1203-1219"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteolysis of tau by granzyme A in tauopathies generates fragments that are aggregation prone. 在牛头脑病中，颗粒酶 A 对牛头脑蛋白的蛋白水解产生易聚集的片段。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-09-18 DOI: 10.1042/BCJ20240007

James P Quinn, Kate Fisher, Nicola Corbett, Stacey Warwood, David Knight, Katherine A B Kellett, Nigel M Hooper

{"title":"Proteolysis of tau by granzyme A in tauopathies generates fragments that are aggregation prone.","authors":"James P Quinn, Kate Fisher, Nicola Corbett, Stacey Warwood, David Knight, Katherine A B Kellett, Nigel M Hooper","doi":"10.1042/BCJ20240007","DOIUrl":"10.1042/BCJ20240007","url":null,"abstract":"Tauopathies, including Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy, are characterised by the aggregation of tau into insoluble neurofibrillary tangles in the brain. Tau is subject to a range of post-translational modifications, including proteolysis, that can promote its aggregation. Neuroinflammation is a hallmark of tauopathies and evidence is growing for a role of CD8+ T cells in disease pathogenesis. CD8+ T cells release granzyme proteases but what role these proteases play in neuronal dysfunction is currently lacking. Here, we identified that granzyme A (GzmA) is present in brain tissue and proteolytically cleaves tau. Mass spectrometric analysis of tau fragments produced on digestion of tau with GzmA identified three cleavage sites at R194-S195, R209-S210 and K240-S241. Mutation of the critical Arg or Lys residues at the cleavage sites in tau or chemical inhibition of GzmA blocked the proteolysis of tau by GzmA. Development of a semi-targeted mass spectrometry approach identified peptides in tauopathy brain tissue corresponding to proteolysis by GzmA at R209-S210 and K240-S241 in tau. When expressed in cells the GzmA-cleaved C-terminal fragments of tau were highly phosphorylated and aggregated upon incubation of the cells with tauopathy brain seed. The C-terminal fragment tau195-441 was able to transfer between cells and promote aggregation of tau in acceptor cells, indicating the propensity for such tau fragments to propagate between cells. Collectively, these results raise the possibility that GzmA, released from infiltrating cytotoxic CD8+ T cells, proteolytically cleaves tau into fragments that may contribute to its pathological properties in tauopathies.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1255-1274"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A hybrid biosynthetic-catabolic pathway for norspermidine production. 生产去甲金丝桃苷的生物合成-代谢混合途径

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2024-09-18 DOI: 10.1042/BCJ20240411

Bin Li, Jue Liang, Margaret A Phillips, Anthony J Michael

{"title":"A hybrid biosynthetic-catabolic pathway for norspermidine production.","authors":"Bin Li, Jue Liang, Margaret A Phillips, Anthony J Michael","doi":"10.1042/BCJ20240411","DOIUrl":"10.1042/BCJ20240411","url":null,"abstract":"The only known pathway for biosynthesis of the polyamine norspermidine starts from aspartate β-semialdehyde to form the diamine 1,3-diaminopropane, which is then converted to norspermidine via a carboxynorspermidine intermediate. This pathway is found primarily in the Vibrionales order of the γ-Proteobacteria. However, norspermidine is also found in other species of bacteria and archaea, and in diverse single-celled eukaryotes, chlorophyte algae and plants that do not encode the known norspermidine biosynthetic pathway. We reasoned that products of polyamine catabolism could be an alternative route to norspermidine production. 1,3-diaminopropane is formed from terminal catabolism of spermine and spermidine, and norspermidine can be formed from catabolism of thermospermine. We found that the single-celled chlorophyte alga Chlamydomonas reinhardtii thermospermine synthase (CrACL5) did not aminopropylate exogenously-derived 1,3-diaminopropane efficiently when expressed in Escherichia coli. In contrast, it completely converted all E. coli native spermidine to thermospermine. Co-expression in E. coli of the polyamine oxidase 5 from lycophyte plant Selaginella lepidophylla (SelPAO5), together with the CrACL5 thermospermine synthase, converted almost all thermospermine to norspermidine. Although CrACL5 was efficient at aminopropylating norspermidine to form tetraamine norspermine, SelPAO5 oxidizes norspermine back to norspermidine, with the balance of flux being inclined fully to norspermine oxidation. The steady-state polyamine content of E. coli co-expressing thermospermine synthase CrACL5 and polyamine oxidase SelPAO5 was an almost total replacement of spermidine by norspermidine. We have recapitulated a potential hybrid biosynthetic-catabolic pathway for norspermidine production in E. coli, which could explain norspermidine accumulation in species that do not encode the known aspartate β-semialdehyde-dependent pathway.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1241-1253"},"PeriodicalIF":4.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Entangling roles of cholesterol-dependent interaction and cholesterol-mediated lipid phase heterogeneity in regulating listeriolysin O pore-formation. 胆固醇依赖性相互作用和胆固醇介导的脂相异质性在调节李斯特溶菌素 O 孔隙形成中的纠缠作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-09-13 DOI: 10.1042/bcj20240184

Kusum Lata,Gregor Anderluh,Kausik Chattopadhyay

{"title":"Entangling roles of cholesterol-dependent interaction and cholesterol-mediated lipid phase heterogeneity in regulating listeriolysin O pore-formation.","authors":"Kusum Lata,Gregor Anderluh,Kausik Chattopadhyay","doi":"10.1042/bcj20240184","DOIUrl":"https://doi.org/10.1042/bcj20240184","url":null,"abstract":"Cholesterol-dependent cytolysins (CDCs) are the distinct class of β-barrel pore-forming toxins (β-PFTs) that attack eukaryotic cell membranes, and form large, oligomeric, transmembrane β-barrel pores. Listeriolysin O (LLO) is a prominent member in the CDC family. As documented for the other CDCs, membrane cholesterol is essential for the pore-forming functionality of LLO. However, it remains obscure how exactly cholesterol facilitates its pore formation. Here, we show that cholesterol promotes both membrane-binding and oligomerization of LLO. We demonstrate cholesterol not only facilitates membrane-binding, it also enhances the saturation threshold of LLO-membrane association, and alteration of the cholesterol-recognition motif (CRM) in the LLO mutant (LLOT515G-L516G) compromises its pore-forming efficacy. Interestingly, such defect of LLOT515G-L516G could be rescued in the presence of higher membrane cholesterol levels, suggesting cholesterol can augment the pore-forming efficacy of LLO even in the absence of a direct toxin-cholesterol interaction. Furthermore, we find the membrane-binding and pore-forming abilities of LLOT515G-L516G, but not those of LLO, correlate with the cholesterol-dependent rigidity/ordering of the membrane lipid bilayer. Our data further suggest that the line tension derived from the lipid phase heterogeneity of the cholesterol-containing membranes could play a pivotal role in LLO function, particularly in the absence of cholesterol binding. Therefore, in addition to its receptor-like role, we conclude cholesterol can further facilitate the pore-forming, membrane-damaging functionality of LLO by asserting the optimal physicochemical environment in membranes. To the best of our knowledge, this aspect of the cholesterol-mediated regulation of the CDC mode of action has not been appreciated thus far.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"8 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0