TBC1D23 mediates Golgi-specific LKB1 signaling

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 27, 2024

Abstract Liver kinase B1 (LKB1), an evolutionarily conserved serine/threonine kinase, is a master regulator of the AMPK subfamily and controls cellular events such as polarity, proliferation, energy homeostasis. Functions mechanisms LKB1-AMPK axis at specific subcellular compartments, lysosome mitochondria, have been established. known to be activated Golgi; however, functions regulatory Golgi apparatus remain elusive. Here, we show that TBC1D23, Golgi-localized protein frequently mutated in neurodevelopment disorder pontocerebellar hypoplasia (PCH), specifically required for LKB1 signaling Golgi. TBC1D23 directly interacts with recruits Golgi, promoting Golgi-specific activation upon stress. Notably, Golgi-targeted expression rescues deficiency zebrafish models. Furthermore, loss causes neurodevelopmental abnormalities zebrafish, which partially recapitulates defects TBC1D23-deficient sustains normal neuronal development via interaction. Our study uncovers mechanism signaling, reveals disrupted Golgi-LKB1 underlies pathogenesis PCH.

Язык: Английский

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Ketogenic diet reshapes cancer metabolism through lysine β-hydroxybutyrylation

Nature Metabolism, Год журнала: 2024, Номер 6(8), С. 1505 - 1528

Опубликована: Авг. 12, 2024

Язык: Английский

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Cargo selective vesicle tethering: The structural basis for binding of specific cargo proteins by the Golgi tether component TBC1D23

Science Advances, Год журнала: 2024, Номер 10(13)

Опубликована: Март 29, 2024

The Golgi-localized golgins golgin-97 and golgin-245 capture transport vesicles arriving from endosomes via the protein TBC1D23. amino-terminal domain of TBC1D23 binds to golgins, carboxyl-terminal captures vesicles, but how it recognizes specific was unclear. A search for binding partners unexpectedly revealed direct carboxypeptidase D syntaxin-16, known cargo proteins captured vesicles. Binding is a threonine-leucine-tyrosine (TLY) sequence present in both next an acidic cluster. crystal structure reveals this TLY motif An also tails other endosome-to-Golgi cargo, these bind Structure-guided mutations that disrupt vitro block vesicle vivo. Thus, attached by previously undescribed mechanism: recognition shared carried vesicle.

Язык: Английский

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The WDR11 complex is a receptor for acidic-cluster-containing cargo proteins

Cell, Год журнала: 2024, Номер 187(16), С. 4272 - 4288.e20

Опубликована: Июль 15, 2024

Язык: Английский

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Trans-Golgi network tethering factors regulate TBK1 trafficking and promote the STING-IFN-I pathway

Cell Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Март 18, 2025

Abstract The cGAS-STING pathway mediates the innate immune response to cytosolic DNA, contributing surveillance against microbial invasion or cellular damage. Once activated, STING recruits TBK1 at trans-Golgi network (TGN), which in turn phosphorylates IRF3 induce type I interferon (IFN-I) expression. In contrast STING, little is known about how transported TGN for activation. Here, we show that multiple tethering factors, a group of proteins involved vesicle capturing, are indispensable STING-IFN-I signaling. Deletion TBC1D23, recently reported factor, mice impairs signaling, but with insignificant effect on STING-NF-κB Mechanistically, TBC1D23 interacts via WASH complex subunit FAM21 and promotes its endosome-to-TGN translocation. Furthermore, factors were reduced aged senescent fibroblasts. summary, our study uncovers key regulators signaling suggests their reduction senescence may produce aberrant

Язык: Английский

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Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 26, 2025

Biogenesis of lysosome-related organelle complex-3 (BLOC-3) is pivotal in vesicle trafficking and has been linked to Hermansky-Pudlak syndrome (HPS). Despite its importance, the structure molecular function BLOC-3 remains elusive. Here, we report Cryo-EM human at 3.2 Å resolution. The complex consists one copy HPS1 HPS4, which tightly associate with each other via their longin domains (LD1 LD3). unique four-helical bundle (4HB) domain involved stabilizing LD1 LD2 domains. Moreover, identify interactions between small GTPases RAB32/38 RAB9A, are essential for biogenesis. Functional assays using zebrafish models confirm significance assembly interaction RAB9A during melanosome Most importantly, our structural information provides an accurate prediction clinical variants associated HPS. In summary, study a comprehensive understanding architecture functional roles BLOC-3, shedding light on HPS pathogenesis. rare autosomal recessive disorder that cause dysfunctions lungs, intestine, kidneys, heart. authors BLOC complex, framework understand how cooperates Rab (RAB32/38 RAB9A) regulate biogenesis organelles.

Язык: Английский

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LTD1 plays a key role in rice tillering regulation through cooperation with CycH1;1 and TFB2 subunits of the TFIIH complex

The Plant Journal, Год журнала: 2025, Номер 122(1)

Опубликована: Март 31, 2025

SUMMARY Tillering contributes greatly to grain yield in rice ( Oryza sativa ). At present, many genes involved tillering regulation have been cloned and characterized. However, the identification of more novel is still necessary fully understand molecular mechanisms regulating tillering. In this study, we isolated a low ‐ dwarf 1 ltd1 ) mutant indica rice. Map‐based cloning MutMap analysis showed that candidate gene LTD1 LOC_Os01g19760 encodes putative FAM91A1 protein with an unknown function plants. ‐complementation ‐RNAi confirmed responsible for phenotype . The localized plasma membrane, endoplasmic reticulum, multi‐vesicular bodies. Furthermore, interaction colocalization assays interacts both TFB2 subunit core subcomplex CycH1;1 cyclin‐dependent kinase‐activating kinase (CAK) TFIIH complex, also CycH1;1. qRT‐PCR demonstrated expression levels most related cell cycle are changed significantly tiller buds, flow cytometry revealed there polyploid nuclei leaves roots, suggesting could be regulation. Taken together, our findings indicated plays key role by involvement through cooperation subunits TFIIH. This work sheds light on biological important agronomic traits

Язык: Английский

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Cocrystal structure reveals the mechanism of FSP1 inhibition by FSEN1

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(22)

Опубликована: Май 29, 2025

FSP1 is an FAD-dependent oxidoreductase that uses NAD(P)H to regenerate the reduced forms of lipophilic quinone antioxidants, such as coenzyme Q10 and vitamin K. These antioxidants function radical scavenging agents prevent propagation lipid peroxidation induction ferroptosis. Although several small-molecule inhibitors have been developed found sensitize cancer cells ferroptosis, our understanding their molecular mechanisms remains limited no structures in complex with its solved. Here, we solve cocrystal structure inhibitor FSEN1, revealing FSEN1 binds within substrate-binding pocket. makes key interactions a critical phenylalanine, which absent mouse FSP1, providing explanation for selectivity human FSP1. conclusions are supported by mutagenesis biochemical cellular assays function. Our findings provide first inhibitor, enhancing mechanism inhibition enabling future rational medicinal chemistry efforts advance therapeutics.

Язык: Английский

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Selective cargo recognition by vesicle tethering factors

The Innovation Life, Год журнала: 2024, Номер unknown, С. 100094 - 100094

Опубликована: Янв. 1, 2024

Язык: Английский

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