TFEB degradation is regulated by an IKK/TrCP2 phosphorylation-ubiquitination cascade
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Marco Sardiello
PROVIDER: MSV000095363 | MassIVE | Wed Jul 17 12:33:00 BST 2024
REPOSITORIES: MassIVE
Similar Datasets
Project description:Untargeted and Targeted analysis of purified and dephosphorylated human TFEB protein after TFEB was enzymatically phosphorylated by IKK2.
2023-10-13 | MSV000093106 | MassIVE
Project description:Nucleosome is a highly dynamic macromolecular complex that is assembled and remodeled by the replacement of major histone variant H2A.Z, thereby affecting nucleosome structure and stability.Here we established two cell lines stably overexpressing wild-type H2A.Z and mutant H2A.Z with ubiquitination deficiency to explore the potential effects caused by H2A.Z ubiquitination. Intriguingly, H2A.Z ubiquitination was first revealed to enhance the stability of H2A-H2A.Z heterotypic nucleosomes. Chromatin immunoprecipitation (ChIP) coupled with high-throughput sequencing (ChIP-Seq) further revealed that H2A.Z ubiquitination played a crucial role in the transcriptional regulation.
2021-06-30 | GSE178363 | GEO
Project description:Cervia LD, Shibue T, Borah AA, Gaeta B, He L, Leung L, Li N, Moyer S, Shim B, Dumont N, Gonzalez A, Bick N, Kazachkova M, Dempster JM, Krill-Burger JM, Piccioni F, Udeshi ND, Olive ME, Carr SA, Root DE, McFarland JM, Vazquez F, Hahn WC. 2022.
Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 726 cancer cell lines to identify selective co-essentiality modules and found a ubiquitination cascade composed of UBA6, BIRC6, KCMF1 and UBR4, which encode an E1, E2 and two heterodimeric E3 subunits, respectively, as required for the survival of a subset of epithelial tumors. Suppressing BIRC6 in cell lines dependent on this ubiquitin ligase complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) signaling by upregulation of the heme-regulated inhibitor (HRI), a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations highlight a ubiquitin ligase complex regulating ISR and identify this complex as a potential therapeutic target for a subset of epithelial cancers.
Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 726 cancer cell lines to identify selective co-essentiality modules and found a ubiquitination cascade composed of UBA6, BIRC6, KCMF1 and UBR4, which encode an E1, E2 and two heterodimeric E3 subunits, respectively, as required for the survival of a subset of epithelial tumors. Suppressing BIRC6 in cell lines dependent on this ubiquitin ligase complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) signaling by upregulation of the heme-regulated inhibitor (HRI), a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations highlight a ubiquitin ligase complex regulating ISR and identify this complex as a potential therapeutic target for a subset of epithelial cancers.
2022-10-27 | MSV000090600 | MassIVE
Project description:Triple-negative breast cancer (TNBC) is a highly aggressive cancer with distant metastasis. Accumulated evidence has demonstrated that exosomes are involved in TNBC metastasis. Elucidating the mechanism underlying TNBC metastasis has important clinical significance. In the present study, exosomes were isolated from clinical specimens and TNBC cell lines. Colony formation, EdU incorporation, wound healing, and transwell assays were performed to examine TNBC cell proliferation, migration, and metastasis. Macrophage polarization was evaluated by flow cytometry and RT-qPCR analysis of polarization markers. A mouse model of subcutaneous tumor was established for assessment of tumor growth and metastasis. RNA pull-down, RIP and Co-IP assays were used for analyzing molecular interactions. Here, we proved that high abundance of circRHCG was observed in exosomes derived from TNBC patients, and increased exosomal circRHCG indicated poor prognosis. Silencing of circRHCG suppressed TNBC cell proliferation, migration, and metastasis. TNBC cell-derived exosomes promoted M2 polarization via delivering circRHCG. Exosomal circRHCG stabilized BTRC mRNA via binding FUS and naturally enhanced BTRC expression, thus promoting the ubiquitination and degradation of TFEB in THP-1 cells. In addition, knockdown of BTRC or overexpression of TFEB counteracted exosomal circRHCG-mediated facilitation of M2 polarization. Furthermore, exosomal circRHCG promoted TNBC cell proliferation and metastasis by facilitating M2 polarization. Knockdown of circRHCG reduced tumor growth, metastasis, and M2 polarization through the BTRC/TFEB axis in vivo. In summary, exosomal circRHCG promotes M2 polarization by stabilizing BTRC and promoting TFEB degradation, thereby accelerating TNBC metastasis and growth. Our study provides promising therapeutic strategies against TNBC.
| S-EPMC10825185 | biostudies-literature
Project description:Posttranslational histone modifications play important roles in regulating chromatin structure and function. Histone H2B ubiquitination and deubiquitination have been implicated in transcriptional regulation, but the function of H2B deubiquitination is not well defined, particularly in higher eukaryotes. Here we report the purification of USP49 as a histone H2B specific deubiquitinase and demonstrate that H2B deubiquitination by USP49 is required for efficient co-transcriptional splicing of a large set of exons. USP49 forms a complex with RVB1 and SUG1, and specifically deubiquitinates histone H2B in vitro and in vivo. USP49 knockdown results in small changes in gene expression, but affects the abundance of over 9,000 isoforms. Exons down-regulated in USP49 knockdown cells show both elevated levels of alternative splicing and a general decrease in splicing efficiency. Importantly, USP49 is relatively enriched at this set of exons. USP49 knockdown increased uH2B levels at these exons as well as upstream 3’ and downstream 5’ intronic splicing elements. Change in H2B ubiquitination level, as modulated by USP49, regulates U1A and U2B association with chromatin and binding to nascent pre-mRNA. Although H3 levels are relatively stable after USP49 depletion, H2B levels at these exons are dramatically increased, suggesting that uH2B may enhance nucleosome stability. Therefore, this study identifies USP49 as a histone H2B specific deubiquitinase and uncovers a critical role for H2B deubiquitination in co-transcriptional pre-mRNA processing events. Examination of histone H2B ubiquitination in wild type and USP49 knockdown cells [ChIP-Seq]
2013-07-28 | E-GEOD-38099 | biostudies-arrayexpress
Project description:Individual stalling of catalytically inactive ribosomes at the start codon triggers ubiquitination of ribosomal protein uS3 and subsequent 18S rRNA decay. While collisions between ribosomes during translation elongation represent a more widespread form of translation perturbation, their impact on ribosome stability remains unknown. Here, we clarify a bifurcation in ubiquitination-mediated ribosome turnover, identifying a collision-induced branch of uS3 ubiquitination and small subunit destabilization in yeast. This pathway eliminates not only non-functional ribosomes but also translationally active ones with a prokaryotic-like decoding center, driven by competition with wild-type ribosomes due to differing translation rates. We further show that endogenous ribosomal subunit stoichiometry shifts toward a small-subunit-shortage state via ubiquitination upon perturbed translation triggered by the anti-cancer drug cisplatin and the growth phase transition. These findings reveal a mechanism by which ribosome dynamics generally affects ribosome stability, implicating ribosome dysfunction, heterogeneity, and stress-related translational disturbances in small subunit degradation.
2025-10-20 | GSE288673 | GEO
Project description:Responses to drought in rice are regulated by transcription factor OsbZIP46 via ABA signaling. This work characterizes a protein MODD that negatively regulates OsbZIP46 activity and stability through HDAC-related chromatin remodeling and OsPUB70-mediated ubiquitination, respectively, to fine tune ABA signaling and drought resistance. Examination of mRNA levels in modd mutants and wild type plants under normal condition.
2016-09-07 | E-GEOD-83075 | biostudies-arrayexpress
Project description:FAT10 is a ubiquitin-like protein modifier that is induced in vertebrates following certain inflammatory stimuli. Its functions and the repertoire of its target substrates have remained elusive. In contrast to ubiquitin, its cellular abundance is tightly controlled by both transcriptional and posttranslational regulation, and it was reported to be rapidly degraded by the proteasome. Here we provide data to indicate that the degradation of FAT10 requires ubiquitination: degradation was inhibited in cells expressing a ubiquitin mutant that cannot be polymerized and in a mutant cell harboring a thermolabile ubiquitin-activating enzyme, E1. Of importance, FAT10 can serve as a degradation signal for otherwise stable proteins, and in this case, too, the targeting to the proteasome requires ubiquitination. Degradation of FAT10 is accelerated after induction of apoptosis, suggesting that it plays a role in prosurvival pathways.
| S-EPMC3248901 | biostudies-literature
Project description:The reversible attachment of ubiquitin governs the interaction, activity and degradation of proteins whereby the type and target of this conjugation determine the biological response. The investigation of this complex and multi-faceted protein ubiquitination mostly relies on painstaking biochemical analyses. Here, we employ recombinant binding domains to identify the UHRF1 dependent ubiquitinated proteins by liquid chromatography tandem mass spectrometry (LC-MS/MS).
2023-01-30 | PXD034335 | Pride
Project description:CRISPR screen in regulatory T cells reveals ubiquitination modulators of Foxp3 stability
| PRJNA588260 | ENA