Septin 9 and phosphoinositides regulate lysosome localization and their association with lipid droplets

iScience, Journal Year: 2022, Volume and Issue: 25(5), P. 104288 - 104288

Published: April 25, 2022

The accumulation of lipid droplets (LDs) in the liver is a hallmark steatosis, which often associated with lysosomal dysfunction. Nevertheless, underlying mechanisms remain unclear. Here, using Huh7 cells loaded oleate as model to study LD metabolism, we show that cellular content and distribution LDs are correlated those lysosome regulated by septin 9. High expression 9 promotes perinuclear clustering lysosomes co-localized Golgi not their surrounding LDs. On other hand, knockdown disperses two organelles colocalize at cell periphery. Rab7 present around these peripheral PtdIns5P binds MTMR3 converts PtdIns(3,5)P2 into PtdIns(5) recapitulates effects By contrast, LD/lysosome co-localization. Overall, our data reveal phosphoinositide/septin 9-dependent mechanism regulates behavior through control association lysosomes.

Language: Английский

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Chlordecone-induced hepatotoxicity and fibrosis are mediated by the proteasomal degradation of septins

Journal of Hazardous Materials, Journal Year: 2024, Volume and Issue: 476, P. 135177 - 135177

Published: July 11, 2024

Chlordecone (CLD) is a pesticide persisting in soils and contaminating food webs. CLD sequestered the liver poorly metabolized into chlordecol (CLDOH). In vitro cell models were used to investigate fate mechanistic effects of CLDOH using multiomics. A 3D-cell model was whether can affect susceptibility metabolic dysfunction-associated steatotic disease (MASLD). Hepatocytes more sensitive than CLDOH. intensively glucuronide conjugate, whereas sequestered. but not induced depletion Septin-2,- 7,- 9,- 10,- 11 due proteasomal degradation. Septin binding with confirmed by surface plasmon resonance. disrupted lipid droplet size increased saturated long-chain dicarboxylic acid production inhibiting stearoyl-CoA desaturase (SCD) abundance. Neither nor steatosis, fibrosis 3D MASLD. To conclude, hepatoxicity specifically driven degradation septins. CLDOH, too rapidly induce septin We show that conversion reduced hepatotoxicity organoids. This suggests protective strategies could be explored reduce CLD.

Language: Английский

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Systems mapping of bidirectional endosomal transport through the crowded cell

Current Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

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SEPT9_i1 and Septin Dynamics in Oncogenesis and Cancer Treatment

Biomolecules, Journal Year: 2024, Volume and Issue: 14(9), P. 1194 - 1194

Published: Sept. 22, 2024

Despite significant advancements in the field of oncology, cancers still pose one greatest challenges modern healthcare. Given cytoskeleton’s pivotal role regulating mechanisms critical to cancer development, further studies cytoskeletal elements could yield new practical applications. Septins represent a group relatively well-conserved GTP-binding proteins that constitute fourth component cytoskeleton. Septin 9 (SEPT9) has been linked diverse spectrum malignancies and appears be most notable septin member category. SEPT9 constitutes biomarker colorectal (CRC) positively correlated with high clinical stage breast cancer, cervical head neck squamous cell carcinoma. SEPT9_i1 represents extensively studied isoform SEPT9, which substantially contributes carcinogenesis, metastasis, treatment resistance. Nevertheless, mechanistic basis oncogenicity remains fully elucidated. In this review, we highlight SEPT9’s SEPT9_i1’s structures interactions Hypoxia Inducible Factor α (HIF-1 α) C-Jun N-Terminal Kinase (JNK), as well discuss contribution aneuploidy, invasiveness, taxane resistance—key phenomena progression malignancies. Finally, emphasize forchlorfenuron other inhibitors potential chemotherapeutics migrastatics.

Language: Английский

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Motor Clustering Enhances Kinesin-driven Vesicle Transport

Published: Oct. 27, 2024

Abstract Intracellular vesicles are typically transported by a small number of kinesin and dynein motors. However, the slow microtubule binding rate kinesin-1 observed in vitro biophysical studies suggests that long-range transport may require high To address discrepancy motor requirements between vivo studies, we reconstituted motility 120-nm-diameter liposomes driven multiple GFP-labeled Consistent with predictions based on previous measurements, found long-distance requires We hypothesized this from observations arise differences organization tested whether clustering can enhance efficiency using DNA scaffold. Clustering just three motors improved liposome travel distances across wide range numbers. Our findings demonstrate that, independent number, arrangement vesicle regulates distance, suggesting explain disparity for transport. Significance Statement frequently long distances, despite having few By reconstituting motors, need copy numbers when randomly distributed surface. further show reduces required emphasizing its potential role enhancing efficiency. highlight significance regulating intracellular suggest clustering, such as scaffolding proteins or lipid domains, influences bidirectional outcomes.

Language: Английский

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