Spatiotemporal recruitment of the ubiquitin-specific protease USP8 directs endosome maturation DOI Open Access
Yue Miao,

Yongtao Du,

Baolei Wang

и другие.

Опубликована: Окт. 18, 2024

The spatiotemporal transition of small GTPase Rab5 to Rab7 is crucial for early-to-late endosome maturation, yet the precise mechanism governing Rab5-to-Rab7 switching remains elusive. USP8, a ubiquitin-specific protease, plays prominent role in endosomal sorting wide range transmembrane receptors and promising target cancer therapy. Here, we identified that USP8 recruited Rab5-positive carriers by Rabex5, guanine nucleotide exchange factor (GEF) Rab5. recruitment dissociates Rabex5 from early endosomes (EEs) meanwhile promotes GEF SAND-1/Mon1. In USP8-deficient cells, level active increased, while signal decreased. As result, enlarged EEs with abundant intraluminal vesicles accumulate digestive lysosomes are rudimentary. Together, our results reveal an important unexpected deubiquitinating enzyme maturation.

Язык: Английский

TBC1D23 mediates Golgi-specific LKB1 signaling DOI Creative Commons
Yingfeng Tu, Qin Yang, Min Tang

и другие.

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

Процитировано

11
β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions DOI
Min Tang, Yingfeng Tu, Yanqiu Gong

и другие.

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

2
FAM91A1–TBC1D23 complex structure reveals human genetic variations susceptible for PCH DOI Creative Commons
Lin Zhao, Huaqing Deng, Qin Yang

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(45)

Опубликована: Окт. 30, 2023

Pontocerebellar hypoplasia (PCH) is a group of rare neurodevelopmental disorders with limited diagnostic and therapeutic options. Mutations in WDR11, subunit the FAM91A1 complex, have been found patients PCH-like symptoms; however, definitive evidence that mutations are causal still lacking. Here, we show depletion results developmental defects zebrafish similar to TBC1D23, an established PCH gene. TBC1D23 directly interact each other cooperate regulate endosome-to-Golgi trafficking KIAA0319L, protein known axonal growth. Crystal structure FAM91A1-TBC1D23 complex reveals binds conserved surface on by assuming Z-shaped conformation. More importantly, interaction between can be used predict risk certain TBC1D23-associated PCH. Collectively, our study provides molecular basis for suggests disrupted endosomal underlies multiple subtypes.

Язык: Английский

Процитировано

9
Molecular structures and function of the autophagosome-lysosome fusion machinery DOI Creative Commons
Jiajie Diao, Calvin K. Yip, Qing Zhong

и другие.

Autophagy Reports, Год журнала: 2024, Номер 3(1)

Опубликована: Фев. 4, 2024

Macroautophagy (also known as autophagy) plays a pivotal role in maintaining cellular homeostasis. The terminal step of the multi-step autophagy degradation pathway involves fusion between cargo-laden, double-membraned autophagosome and lytic organelle lysosome/vacuole. Over past decade, various core components molecular machinery that execute this critical event have been identified. This review highlights recent advances understanding structures, biochemical functions, regulatory mechanisms key highly sophisticated including SNARE fusogens, tethering factors, Rab GTPases associated guanine nucleotide exchange other accessory factors.

Язык: Английский

Процитировано

3
SDC4 drives fibrotic remodeling of the intervertebral disc under altered spinal loading DOI Open Access
Kimheak Sao, Makarand V. Risbud

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 14, 2025

Alterations in physiological loading of the spine are deleterious to intervertebral disc health. The caudal region Ca3-6 that experiences increased flexion, showed degeneration young adult mice. Given role Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan matrix catabolism and mechanosensing, we investigated if deletion could mitigate this loading-dependent phenotype. Notably, at spinal levels Ca3-6, Sdc4- KO mice did not exhibit collagen fibril fibronectin deposition NP compartment or alterations crosslinks observed wild-type Similarly, unlike mice, cells Sdc4 -KO retained transgelin (TGLN) expression absence COL X deposition, pointing preservation their notochordal characteristics. Proteomic analysis revealed tissues responded abnormal by increasing abundance proteins associated with extracellular remodeling, chondrocyte development, contractility. downregulated suggested decreased vesicle transport, autophagy-related pathway, RNA quality control regulation. proteome from dynamin-mediated endocytosis, DNA may underscore protection flexion-induced degeneration. Our study highlights important SDC4 fine-tuning cellular homeostasis production environment subjected altered loading.

Язык: Английский

Процитировано

0
Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome DOI Creative Commons
Yong Xin, Guowen Jia, Qin Yang

и другие.

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

Процитировано

0
ESCRTing the RABs through conversion DOI Creative Commons
Jachen A. Solinger,

Daniel P. Ott,

Anne Spang

и другие.

Biochemical Society Transactions, Год журнала: 2025, Номер 53(02), С. 431 - 445

Опубликована: Апрель 1, 2025

The endosomal system is essential for the intra- and intercellular communication in cells multicellular organisms. It involved secretion of signaling factors serves as a venue receptors from plasma membrane, which are endocytosed after ligand binding. Many internalized receptor–ligand complexes numerous other proteins arrive at Rab5-positive early endosome, where they will be sorted. Cargoes marked with ubiquitin bound by sorting complex required transport (ESCRT)-0 ESCRT-I to initiate their degradation. remaining cargoes recycled back membrane or trans-Golgi network. To degrade ubiquitinated cargoes, endosome has mature into late structure, multivesicular body (MVB). This procedure requires Rab5-to-Rab7 conversion, mediated RABEX5-MON1/CCZ1 RabGEF cascade. Moreover, destined degradation have packaged intraluminal vesicles (ILVs) through ESCRT-III Vps4. matured MVB finally fuses lysosome cargo. Although ESCRT-mediated ILV formation Rab conversion well-characterized processes during maturation, it remained until recently unclear whether these connected. Lately, several studies were published illuminating relationship ESCRT functions conversion. Here, we review current knowledge on role machinery cargo RABEX5 regulation MON1/CCZ1-mediated maturation. propose model regulatory

Язык: Английский

Процитировано

0
Spatiotemporal recruitment of the ubiquitin-specific protease USP8 directs endosome maturation DOI Creative Commons
Yue Miao,

Yongtao Du,

Baolei Wang

и другие.

eLife, Год журнала: 2024, Номер 13

Опубликована: Апрель 16, 2024

The spatiotemporal transition of small GTPase Rab5 to Rab7 is crucial for early-to-late endosome maturation, yet the precise mechanism governing Rab5-to-Rab7 switching remains elusive. USP8, a ubiquitin-specific protease, plays prominent role in endosomal sorting wide range transmembrane receptors and promising target cancer therapy. Here, we identified that USP8 recruited Rab5-positive carriers by Rabex5, guanine nucleotide exchange factor (GEF) Rab5. recruitment dissociates Rabex5 from early endosomes (EEs) meanwhile promotes GEF SAND-1/Mon1. In USP8-deficient cells, level active increased, while signal decreased. As result, enlarged EEs with abundant intraluminal vesicles accumulate digestive lysosomes are rudimentary. Together, our results reveal an important unexpected deubiquitinating enzyme maturation.

Язык: Английский

Процитировано

1
Spatiotemporal recruitment of the ubiquitin-specific protease USP8 directs endosome maturation DOI Creative Commons
Yue Miao,

Yongtao Du,

Baolei Wang

и другие.

eLife, Год журнала: 2024, Номер 13

Опубликована: Ноя. 22, 2024

The spatiotemporal transition of small GTPase Rab5 to Rab7 is crucial for early-to-late endosome maturation, yet the precise mechanism governing Rab5-to-Rab7 switching remains elusive. USP8, a ubiquitin-specific protease, plays prominent role in endosomal sorting wide range transmembrane receptors and promising target cancer therapy. Here, we identified that USP8 recruited Rab5-positive carriers by Rabex5, guanine nucleotide exchange factor (GEF) Rab5. recruitment dissociates Rabex5 from early endosomes (EEs) meanwhile promotes GEF SAND-1/Mon1. In USP8-deficient cells, level active increased, while signal decreased. As result, enlarged EEs with abundant intraluminal vesicles accumulate digestive lysosomes are rudimentary. Together, our results reveal an important unexpected deubiquitinating enzyme maturation.

Язык: Английский

Процитировано

1
Spatiotemporal recruitment of the ubiquitin-specific protease USP8 directs endosome maturation DOI Creative Commons
Yue Miao,

Yongtao Du,

Baolei Wang

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 11, 2024

Abstract The spatiotemporal transition of small GTPase Rab5 to Rab7 is crucial for early-to-late endosome maturation, yet the precise mechanism governing Rab5-to-Rab7 switching remains elusive. USP8, a ubiquitin-specific protease, plays prominent role in endosomal sorting wide range transmembrane receptors and promising target cancer therapy. Here, we identified that USP8 recruited Rab5-positive carriers by Rabex5, guanine nucleotide exchange factor (GEF) Rab5. recruitment dissociates Rabex5 from early endosomes (EEs) meanwhile promotes GEF SAND-1/Mon1. In USP8-deficient cells, level active increased, while signal decreased. As result, enlarged EEs with abundant intraluminal vesicles accumulate digestive lysosomes are rudimentary. Together, our results reveal an important unexpected deubiquitinating enzyme maturation.

Язык: Английский

Процитировано

0