VCP enhances autophagy-related osteosarcoma progression by recruiting USP2 to inhibit ubiquitination and degradation of FASN DOI Creative Commons
Shijiang Wang, Jiangbo Nie, Huinan Jiang

и другие.

Cell Death and Disease, Год журнала: 2024, Номер 15(11)

Опубликована: Ноя. 3, 2024

Abstract Osteosarcoma (OS) is a highly aggressive malignant tumor with high rate of disability and mortality rates, dysregulated autophagy crucial factor in cancer. However, the molecular mechanisms that regulate OS remain unclear. This study aimed to explore key molecules affect their regulatory mechanisms. We found fatty acid synthase (FASN) was significantly increased activated models promoted proliferation an autophagy-dependent manner, as detected by LC3 double-labeled fluorescence confocal microscopy, western blotting, transmission electron microscopy (TEM), cell functional experiments. Furthermore, co-immunoprecipitation combined mass spectrometry (Co-IP/MS), ubiquitination modification, docking, protein truncation methods were used identify FASN-interacting proteins analyze effects on OS. Valosin-containing (VCP) enhanced FASN stability recruiting ubiquitin specific peptidase-2 (USP2) remove K48-linked chains from FASN; domain 2 VCP amino sequence () USP2 critical for interactions. Gain- loss-of-function experiments showed inhibition or attenuated stimulatory effect overexpression phenotypes cells vitro vivo. Notably, micro-CT indicated induced severe bone destruction nude mice, which abrogated downregulation. In summary, recruits stabilize deubiquitylation, thereby activating promoting progression. The identification VCP/USP2/FASN axis, mediates regulation, provides important insights into underlying offers potential diagnostic therapeutic strategies patients

Язык: Английский

Targeting of client proteins to the VCP/p97/Cdc48 unfolding machine DOI Creative Commons
Hemmo Meyer, Johannes van den Boom

Frontiers in Molecular Biosciences, Год журнала: 2023, Номер 10

Опубликована: Фев. 7, 2023

The AAA+ ATPase p97 (also called VCP or Cdc48) is a major protein unfolding machine with hundreds of clients in diverse cellular pathways that are critical for cell homeostasis, proliferation and signaling. In this review, we summarize recent advances understanding how client proteins targeted to the facilitate degradation strip from binding partners regulation. We describe an elaborate system governed by at least two types alternative adapters. Ufd1-Npl4 adapter along accessory adapters targets ubiquitylated majority uses ubiquitin as universal tag. contrast, family SEP-domain such p37 can target directly ubiquitin-independent manner. Despite different targeting strategies, both converge inserting into pore initiate peptide threading mechanism through central channel drives unfolding, extraction membranes complex disassembly processes.

Язык: Английский

Процитировано

24
Therapeutic Potential of Natural Compounds from Herbs and Nutraceuticals in Alleviating Neurological Disorders: Targeting the Wnt Signaling Pathway DOI
Lei Li, Lin Wang, Lijuan Zhang

и другие.

Journal of Agricultural and Food Chemistry, Год журнала: 2024, Номер 72(5), С. 2411 - 2433

Опубликована: Янв. 29, 2024

As an important signaling pathway in multicellular eukaryotes, the Wnt participates a variety of physiological processes. Recent studies have confirmed that plays role neurological disorders such as stroke, Alzheimer's disease, and Parkinson's disease. The regulation by natural compounds herbal medicines nutraceuticals has emerged potential strategy for development new drugs disorders.

Язык: Английский

Процитировано

12
Structural basis of human VANGL-PRICKLE interaction DOI Creative Commons
Yanyi Song,

Shuyi Jian,

Junlin Teng

и другие.

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

Опубликована: Янв. 3, 2025

Planar cell polarity (PCP) is an evolutionarily conserved process for development and morphogenesis in metazoans. The well-organized pattern cells established by the asymmetric distribution of two core protein complexes on opposite sides membrane. Van Gogh-like (VANGL)-PRICKLE (PK) pair one these key regulators; however, their structural information detailed functions have been unclear. Here, we present five cryo-electron microscopy structures human VANGL1, VANGL2, with PK1 at resolutions 2.2–3.0 Å. Through biochemical imaging experiments, decipher molecular details VANGL-PK interaction. Furthermore, reveal that can target VANGL-containing intracellular vesicles to peripheral These findings provide a solid foundation understand explicit interaction between VANGL PK while opening new avenues subsequent studies PCP pathway. authors VANGL2 PK1, unveiling underpinnings paving way future investigations into planar pathway

Язык: Английский

Процитировано

1
Rhpn2 regulates the development and function of vestibular sensory hair cells through the RhoA signaling in zebrafish DOI

Yu-Bei Dai,

Qianqian Li,

Jiaju Deng

и другие.

Journal of genetics and genomics/Journal of Genetics and Genomics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

1
Vangl as a Master Scaffold for Wnt/Planar Cell Polarity Signaling in Development and Disease DOI Creative Commons

Courtney A. Dreyer,

Kacey VanderVorst,

Kermit L. Carraway

и другие.

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Май 11, 2022

The establishment of polarity within tissues and dynamic cellular morphogenetic events are features common to both developing adult tissues, breakdown these programs is associated with diverse human diseases. Wnt/Planar cell (Wnt/PCP) signaling, a branch non-canonical Wnt critical the maintenance in epithelial as well motility proper embryonic development. In Wnt/PCP-mediated planar relies upon asymmetric distribution core proteins establish polarity, but requirement for this remains unclear. However, polarized migratory cells, Wnt/PCP-specific transmembrane protein Vangl required appears serve scaffold which pathway components positive negative regulators Wnt/PCP signaling assemble. current literature suggests that multiple interaction domains allow binding partners context- tissue-specific complexes. review we discuss role master tissue address how dysregulated disease.

Язык: Английский

Процитировано

26
A proteogenomic analysis of cervical cancer reveals therapeutic and biological insights DOI Creative Commons
Jing Yu, Xiuqi Gui,

Yanmei Zou

и другие.

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

Опубликована: Ноя. 22, 2024

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses threat women's low-income countries. Here, we perform comprehensive proteogenomic profiling CC tumors obtained from 139 Chinese women. Integrated analysis links genetic aberrations downstream pathogenesis-related pathways reveals landscape HPV-associated multi-omic changes. EP300 is found enhance acetylation FOSL2-K222, consequently accelerating malignant proliferation cells. Proteomic stratification identifies three patient subgroups with distinct features prognosis, alterations, immune infiltration, post-translational modification regulations. PRKCB further identified as potential radioresponse-related biomarker patients. This study provides valuable resource for researchers clinicians delve into molecular basis CC, identify treatments ultimately advance clinical practice. Cervical problem many regions. authors patients; they reveal proteomic associated biological features, response radiotherapy.

Язык: Английский

Процитировано

6
RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy DOI Creative Commons
Tomasz Radaszkiewicz, Michaela Nosková, Kristína Gömöryová

и другие.

eLife, Год журнала: 2021, Номер 10

Опубликована: Окт. 26, 2021

RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that also a noncanonical WNT5A-induced signaling in human cells. Analysis the interactome using BioID immunoprecipitation showed can interact with core receptor complex components dedicated to Wnt pathway such as ROR1, ROR2, VANGL1, VANGL2. triggers VANGL2 ubiquitination proteasomal degradation clathrin-dependent internalization ROR1 inhibits ROR2 activation. These activities are physiologically relevant block pro-metastatic WNT5A melanoma. responses WNT5A, which results suppression invasive properties melanoma Furthermore, prevented WNT5A-assisted development resistance BRAF V600E MEK inhibitors. Next, acted suppressor improved response targeted therapies vivo. In line these findings, expression decreases during progression RNF43-low patients have worse prognosis. conclude newly discovered WNT5A-mediated biological desensitizes cells WNT5A.

Язык: Английский

Процитировано

33
Cooperative assembly of p97 complexes involved in replication termination DOI Creative Commons

Olga V. Kochenova,

Sirisha Mukkavalli, Malavika Raman

и другие.

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Ноя. 3, 2022

Abstract The p97 ATPase extracts polyubiquitylated proteins from diverse cellular structures in preparation for destruction by the proteasome. functions with Ufd1-Npl4 and a variety of UBA-UBX co-factors, but how complexes assemble on ubiquitylated substrates is unclear. To address this, we investigated disassembles CMG helicase after it during replication termination. We show that recruitment to requires protein Ubxn7, conversely, stable Ubxn7 binding . This cooperative assembly involves interactions between p97, Ufd1-Npl4, ubiquitin. Another co-factor, Faf1, partially compensates loss Ubxn7. Surprisingly, Ufd1-Npl4-Ubxn7 Ufd1-Npl4-Faf1 also cooperatively unanchored ubiquitin chains. propose substrate-independent recognition chains allows recognize an unlimited number while avoiding formation partial, inactive complexes.

Язык: Английский

Процитировано

20
The role of Rho GTPase family in cochlear hair cells and hearing DOI Creative Commons
Dong Liu,

Gong Jie,

Yu-Bei Dai

и другие.

Neural Regeneration Research, Год журнала: 2023, Номер 18(10), С. 2167 - 2167

Опубликована: Янв. 1, 2023

Rho GTPases are essential regulators of the actin cytoskeleton. They involved in various physiological and biochemical processes such as regulation cytoskeleton dynamics, development, proliferation, survival, regeneration. During development cochlear hair cells, activated by extracellular signals through membrane receptors to further stimulate multiple downstream effectors. Specifically, RhoA, Cdc42, Rac1, members classical subfamily GTPase family, regulate maintenance cilia inducing polymerization monomers stabilizing filaments. In addition, they also normal morphology orientation ciliary bundles auditory which is an important element cell polarity regulation. Moreover, actin-related pathways mediated Rac1 play a role motility outer indicating that function crucial highly polar sensory system. this review, we focus on expression cells how these small molecules participate bundle morphogenesis movement. We discuss progress current research investigating use drug targets for deafness treatment.

Язык: Английский

Процитировано

13
Mitochondrial amidoxime‐reducing component 1 p.Ala165Thr increases protein degradation mediated by the proteasome DOI Creative Commons
Tanmoy Dutta, Kavitha Sasidharan, Ester Ciociola

и другие.

Liver International, Год журнала: 2024, Номер 44(5), С. 1219 - 1232

Опубликована: Фев. 20, 2024

Abstract Objective Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a global health concern with no effective and specific drug treatment available. The rs2642438 minor allele in mitochondrial amidoxime‐reducing component 1 ( MARC1 ) results an aminoacidic substitution (p.Ala165Thr) associates protection against MASLD. However, the mechanisms behind this protective effect are unknown. In study, we examined consequences of on protein stability subcellular localization. Methods We overexpressed human A165 (wild‐type) or 165T (mutant) vivo mice vitro hepatoma cells (HepG2 HuH‐7), generated several mutants at position 165 by situ mutagenesis then levels. also HepG2 stably overexpressing to test Results overexpression resulted lower levels than both vitro. Similarly, any mutant showed compared wild‐type protein. that polyubiquitinated its degradation accelerated through lysine‐48 ubiquitin‐mediated proteasomal degradation. does not affect Conclusions This study shows alanine crucial for stability, threonine leads hypomorphic variant due Our result supports notion lowering hepatic level may be successful therapeutic strategy treating

Язык: Английский

Процитировано

5