Life Science Alliance最新文献

{"title":"Glycolysis inhibition in tuberculosis-driven metabolic rewiring reduces HIV-1 spread in macrophages.","authors":"Zoï Vahlas, Clara Deyts, Steven Fried, Myriam Ben Neji, Maxime Pingret, Natacha Faivre, Sarah C Monard, Quentin Hertel, Mariano Maio, Joaquina Barros, Alexandre Lucas, Thien Phong Vu Manh, Marcelo Corti, Renaud Poincloux, Fabien Blanchet, Brigitte Raynaud-Messina, Fabien Letisse, Olivier Neyrolles, Geanncarlo Lugo-Villarino, Luciana Balboa, Christel Vérollet","doi":"10.26508/lsa.202503333","DOIUrl":"10.26508/lsa.202503333","url":null,"abstract":"<p><p>Tuberculosis (TB) is a significant aggravating factor in individuals living with HIV-1, the causative agent for AIDS. Both <i>Mycobacterium tuberculosis</i> (Mtb), the bacterium responsible for TB, and HIV-1 target macrophages. Understanding how Mtb subverts these cells may facilitate the identification of new druggable targets. Here, we explored how TB can induce macrophages to form tunneling nanotubes (TNT), promoting HIV-1 spread. We found that TB triggers metabolic rewiring of macrophages, increasing their glycolytic ATP production. Using several pharmacological inhibitors, glucose deprivation, and glucose or galactose supplementation, we discovered that disrupting aerobic glycolysis significantly reduces HIV-1 infection in these macrophages. Glycolysis is essential for tunneling nanotubes formation, which facilitates viral transfer and cell-to-cell fusion. Importantly, HIF-1α activation contributes to these processes. Overall, these data might facilitate the development of targeted therapies aimed at inhibiting HIF-1α-dependent glycolytic activity in TB-induced immunomodulatory macrophages to ultimately halt HIV-1 dissemination in coinfected patients.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12920055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetyl-carnitine improves hyperactivity and learning deficits in <i>KAT6A</i> haploinsufficient mice.","authors":"Samantha Eccles, Hannah K Vanyai, Maria I Bergamasco, Shezlie Malelang, Havva Pehlivanoglu, Alexandra L Garnham, Nishika Ranathunga, Marnie E Blewitt, Adam P Vogel, Gordon K Smyth, Anthony J Hannan, Tim Thomas, Anne K Voss","doi":"10.26508/lsa.202503549","DOIUrl":"10.26508/lsa.202503549","url":null,"abstract":"<p><p>Pathogenic variants in one allele of the <i>KAT6A</i> gene encoding the histone acetyltransferase KAT6A (MOZ, MYST3) cause Arboleda-Tham syndrome (ARTHS), characterised by developmental delay, cognitive impairment, and autism-like behaviours. As histone acetylation is reversible, and brain development continues after birth, treatments that address deficits in histone acetylation may ameliorate the condition. Here, we examined the effects of ARTHS mutations on histone acetylation in human cells and the effects of heterozygous loss of <i>Kat6a</i> in mice (<i>Kat6a</i> ^<i>+/-</i> ) on learning, memory, activity, and sociability. We found that KAT6A was required for normal levels of histone H3 lysine 23 acetylation (H3K23ac) in human cells and mouse brain. <i>Kat6a</i> ^<i>+/-</i> mice displayed hyperactivity and learning, memory, and sociability deficits compared with WT mice. Treatment with the acetyl-donor, acetyl-L-carnitine (ALCAR) resulted in the rescue of H3K23ac levels in mouse brain and amelioration of the hyperactivity and learning impairments. Our results suggest that some individuals with ARTHS might benefit from ALCAR treatment. However, the suitability of ALCAR treatment would depend on the specific <i>KAT6A</i> variant and should be discussed with health professionals.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12912912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connexin 32 constrains a mesenchymal-like switch in differentiated urothelium and luminal cancers.","authors":"Jennifer Hinley, Simon C Baker, Andrew S Mason, Grigorios Kyriazis, Omar Masood, Jennifer Southgate","doi":"10.26508/lsa.202503427","DOIUrl":"10.26508/lsa.202503427","url":null,"abstract":"<p><p>The molecular programming of epithelial wound repair provides the origin for the signalling pathways that drive the growth and spread of carcinoma cells. Urothelium is the mitotically quiescent, barrier-forming transitional epithelium of the urinary tract, characterised by uniquely specialised superficial cells and a remarkable regenerative capacity in response to damage. Connexin 32 (Cx32) was expressed by differentiated human urothelium where it predominantly localised to the basolateral borders of superficial urothelial cells. Suppression of Cx32 gap junction intercellular communication did not affect differentiation but instigated the switch to a highly migratory, wound healing phenotype marked by TGFβ-SMAD signalling, ECM-remodelling, and induction of mesenchymal and cell-cycle markers. Immunohistological classification of muscle-invasive bladder cancers revealed Cx32 expression to be informative in luminal tumour biology, with non-membrane localised Cx32 defining a Ki67-high, vimentin-expressing, and TGFβ-activated subset of luminal tumours. Our findings identify Cx32 cell-cell communication as suppressing migratory and proliferative behaviours in normal urothelial differentiation and suggest that Cx32 assessment, within the context of luminal muscle-invasive bladder cancer, can predict more invasive biology. This reveals the potential for differentiated cancers to exhibit EMT.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12912911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and functional characterisation of ATF2 nuclear import reveals paralogue-selective importin-α recognition and a non-canonical NLS formed in trans.","authors":"Seyed Mohammad Ghafoori, Silvia Pavan, Trinh Xuan Duc, Sepehr Nematollahzadeh, Gayle F Petersen, Gualtiero Alvisi, Jade K Forwood","doi":"10.26508/lsa.202503543","DOIUrl":"10.26508/lsa.202503543","url":null,"abstract":"<p><p>Activating transcription factor 2 (ATF2) is a member of the AP-1 superfamily that regulates essential cellular processes through its activity as a nuclear transcription factor. Although ATF2 plays well-established roles in neurodevelopment, inflammation, and cancer, the mechanisms underlying its nuclear localisation remain poorly characterised. Here, we investigate the structural and functional basis of ATF2 nuclear import via the classical importin-α/β1 (IMPα/β1) pathway. Using quantitative in vitro binding assays, we demonstrate that ATF2 interacts with multiple IMPα paralogues. Fluorescence polarisation measurements reveal the highest binding affinity for IMPα1, with progressively weaker interactions observed for IMPα3, IMPα5, and IMPα7. Crystallographic analysis of ATF2 bound to IMPα1 identifies two basic clusters that are important for interaction: site 1 (³⁵³EKRRK³⁵⁷), which binds the major site of IMPα1, and site 2 (³⁷²KRK³⁷⁴), which binds the minor site. Mutation of key residues confirms the importance of both motifs, with site 1 contributing more substantially to binding. Quantitative confocal laser scanning microscopy analysis in HEK293A cells supports these findings, showing that mutation of both clusters is required to fully abolish ATF2 nuclear localisation. Inhibition of classical nuclear import using Bimax2 significantly reduces nuclear accumulation, whereas treatment with leptomycin B confirms a role of chromosomal region maintenance 1 (CRM1)-mediated nuclear export. Notably, ATF2 mutants incapable of nuclear import can localise to the nucleus when co-expressed with c-Jun, indicating that c-Jun can facilitate ATF2 nuclear import via heterodimerisation. Together, these results establish that ATF2 enters the nucleus through IMPα recognition of two basic clusters and highlight the redundancy and complexity of ATF2 nuclear trafficking mechanisms.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12894764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytohesin-2 is essential for the perinatal development of mice and regulates Golgi volume.","authors":"Carsten Küsters, Bettina Jux, Farhad Shakeri, Sebastian Kallabis, Felix Meissner, Waldemar Kolanus","doi":"10.26508/lsa.202503429","DOIUrl":"10.26508/lsa.202503429","url":null,"abstract":"<p><p>Cytohesin proteins are guanine nucleotide exchange factors (GEFs) for ARF GTPases, particularly ARF1 and ARF6. Although <i>Arf1</i> and <i>Arf6</i> deficiency leads to embryonic lethality, the in vivo roles of cytohesins remain poorly characterized. In this study, we investigated the functions of cytohesin-2 both in vivo and in vitro. Strikingly, full knockout of cytohesin-2 in mice results in perinatal lethality within 20 h of birth. Employing mass spectrometry-based organellar proteomics for the cellular analysis of cytohesin-2 function, we discovered an altered Golgi apparatus in cytohesin-2-deficient C2 myoblasts. Specifically, immunofluorescence analysis demonstrated a significant reduction in Golgi volume compared with the control, which was restored by reintroduction of cytohesin-2 in an ARF-GEF-independent manner. Moreover, we discovered that canonical Golgi functions are impaired in cytohesin-2 deficiency: Peanut agglutinin staining showed a significant reduction in galactose/N-acetyl-galactosamine at the cell level. In addition, global protein secretion was markedly reduced in neonatal cytohesin-2 knockout mice, as determined by quantitative mass spectrometry-based proteomics. Together, our findings establish cytohesin-2 as an essential regulator of perinatal development and as a mediator of Golgi maintenance.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12894763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated Piezo levels cause structural and functional alterations in <i>Drosophila</i> garland nephrocytes.","authors":"Paris Hazelton-Cavill, Karl K Alornyo, Michelle Bouchard, Kristina Schulz, Tobias B Huber, Barry Denholm, Sybille Koehler","doi":"10.26508/lsa.202503515","DOIUrl":"10.26508/lsa.202503515","url":null,"abstract":"<p><p>Podocytes, epithelial cells of the glomerular filtration barrier, are constantly exposed to biomechanical forces. These include hydrostatic pressure and shear stress, which increase during diseases such as hypertension or diabetes. To sense and respond to such changes in their physical environment, podocytes express mechanosensors and mechanotransducers. To deepen our knowledge about renal mechanotransduction mechanisms, we used <i>Drosophila</i> nephrocytes. Nephrocytes and mammalian podocytes are highly similar in morphology and molecular make-up of the filtration barrier; thus, nephrocytes are considered the homologue cells to podocytes. In addition, nephrocytes also experience biomechanical forces because of haemolymph movement. Here, we investigated the role of the mechanotransducer Piezo in larval garland nephrocytes. Depletion of Piezo produces only a mild functional phenotype, whereas elevated Piezo levels result in a severe phenotype with functional and morphological disturbances. Increased Piezo levels also cause the accumulation of actin stress fibres, increased Cubilin expression, more acidic vesicles, increased mitochondrial mass and/or activity, and elevated superoxide levels.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12885765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146150238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of thymidylate synthase inhibitors differ in genomic uracilation and mutagenic potential.","authors":"Eszter Holub, Gábor Papp, Hajnalka Laura Pálinkás, Milda Blanka Szajkó, Richard Izrael, Gergely Róna, Beáta G Vértessy, Angéla Békési","doi":"10.26508/lsa.202503352","DOIUrl":"10.26508/lsa.202503352","url":null,"abstract":"<p><p>Genomic uracil and its respective repair play key roles in colorectal, gastric, and other solid tumor therapies targeting thymidylate biosynthesis. Previously, we established that treating HCT116 colon cancer cell lines with either raltitrexed (RTX) or 5-fluoro-2'-deoxyuridine (5FdUR), two potent inhibitors of thymidylate synthase, results in characteristic genomic uracil patterns. Here, we focus on drug-specific differences in the genomic uracil profiles and their associations with altered cytotoxicity and drug-induced mutagenesis. We demonstrated that biased uracilation preferentially affects functionally related genes in a drug-specific manner, highlighting the biological significance of genomic uracilation. Mutational analysis further revealed a significant increase in the frequency of C-to-T somatic transitions, selectively in response to high-dose 5FdUR treatment, in DNA repair-deficient cells. The mutational spectra and the clustered nature of these transitions suggested the involvement of APOBEC3 DNA cytidine deaminases, several of which were induced under these conditions. Notably, this mutagenic response coincides with decreased cytotoxicity compared with the low-dose 5FdUR or any efficient doses of RTX, providing insights that may be relevant for personalized cancer therapy.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12881662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Notch1 intracellular domain orchestrates mechanotransduction of fluid shear stress.","authors":"Tania Singh, Kyle A Jacobs, William J Polacheck, Matthew L Kutys","doi":"10.26508/lsa.202503599","DOIUrl":"10.26508/lsa.202503599","url":null,"abstract":"<p><p>Hemodynamic shear stress regulates endothelial phenotype through activation of Notch1 signaling, yet the mechanistic basis for this activation is unclear. Here, we establish a fluid shear stress-dependent mechanism of Notch1 activation that is distinct from canonical ligand trans-endocytosis. Application of unidirectional laminar flow triggers the rapid spatial polarization of full-length Notch1 heterodimers into downstream membrane microdomains. Unlike canonical transactivation, Notch1 receptors are cis-endocytosed into the receptor-bearing cell within polarized microdomains. We discover that the Notch1 intracellular domain critically orchestrates receptor polarization and proteolytic cleavage in response to flow, but is dispensable for canonical ligand transactivation. Shear stress increases intracellular domain interaction with annexin A2 and caveolar proteins, which control Notch1 cis-endocytosis and proteolytic activation. These findings define a flow-specific Notch1 mechanotransduction mechanism linking receptor polarization and endocytosis with proteolytic activation and illuminate a new pathway by which mechanical forces integrate with Notch receptor activation.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12877406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclic stretch induces autophagy-mediated focal adhesion remodeling and activates mitochondria.","authors":"Lukas Lövenich, Bahareh Rahimi, Henrique Baeta, Maithreyan Kuppusamy, Moritz Walkenbach, Frederik Rastfeld, Georg Dreissen, Ronald Wein, Jörg Höhfeld, Rudolf Merkel, Pitter F Huesgen, Bernd Hoffmann","doi":"10.26508/lsa.202503347","DOIUrl":"10.26508/lsa.202503347","url":null,"abstract":"<p><p>Mammalian cells are continuously exposed to internally generated or externally applied mechanical stimuli. Mechanosensitive proteins enable cells to sense mechanical stress and induce protective mechanisms like autophagy and cytoskeletal reorientation. However, how these contribute to cellular and tissue adaptations remains largely unknown. Here, we studied the response of rat smooth muscle cells (A7r5) to uniaxial cyclic stretch. Stretching induced autophagy and adaptive actin fiber reorientation. Inhibiting autophagy using chloroquine or expressing a Bag3 (T285D-S289D) phosphosite mutant that impairs chaperone-assisted selective autophagy (CASA) delayed reorientation. Proteomic analysis revealed a depletion of cytoskeletal and focal adhesion proteins after stretching, which was attenuated by autophagy inhibition. Stretching caused a reduction in focal adhesion (FA) size, and the remodeled FAs reoriented perpendicularly to the strain direction. Concurrently, prolonged stretching activated mitochondria, and inhibiting mitochondrial ATP synthesis slowed actin reorientation, suggesting that mitochondrial activity supports the mechanoresponse. Our findings highlight the role of autophagy and mitochondria in the structural remodeling of cells upon adaptation to mechanical stress.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12877405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NCOA4 initiates ferritinophagy by avidly binding GATE16 using two short linear interaction motifs.","authors":"April Lee, Joseph H Davis","doi":"10.26508/lsa.202503611","DOIUrl":"10.26508/lsa.202503611","url":null,"abstract":"<p><p>Cells carefully regulate cytosolic iron, which is a vital enzymatic cofactor, yet is toxic in excess. In mammalian cells, surplus iron is sequestered in ferritin cages that, in iron-limiting conditions, can be degraded through the selective autophagy pathway ferritinophagy to liberate free iron. Prior work identified the ferritinophagy receptor protein NCOA4, which links ferritin and LC3/GABARAP-family member GATE16, effectively tethering ferritin to the autophagic machinery. Here, we elucidate the molecular mechanism underlying this interaction, discovering two short linear motifs in NCOA4 that each bind GATE16 with weak affinity. These binding motifs are highly avid and, in concert, support high-affinity NCOA4•GATE16 complex formation. We further find the minimal NCOA4^383-522 fragment bearing these motifs is sufficient for ferritinophagy and that both motifs are necessary for this activity. This work suggests a general mechanism wherein selective autophagy receptors can distinguish between the inactive pools of monomeric LC3/GABARAPs and the active oligomerized forms that drive autophagy. Finally, we find that iron decreases affinity of the NCOA4^383-522 fragment for GATE16, providing a plausible mechanism for iron-dependent regulation of ferritinophagy.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"9 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12872393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}