Dataset Information

Multi-Omics Integration Highlights the Role of Ubiquitination in Endometriosis Fibrosis

ABSTRACT: In this study, we comprehensively profiled the ubiquitination landscape of endometriosis for the first time. Through proteomics, transcriptomics, and ubiquitylomics analyses of endometrial tissues from two patient cohorts, we uncovered significant dysregulation of ubiquitin-related enzymes and ubiquitinated proteins. By comparing tissues in pathological and healthy states, we delineated ubiquitinated proteins associated with the etiology of endometriosis and revealed their regulatory roles in relevant biological processes. We observed a pivotal role of ubiquitination in the fibrotic process, particularly in processes related to the activity of myofibroblasts and collagen deposition in ectopic tissues. Besides, we uncovered the downregulation of the E3 ubiquitin ligase TRIM33 in endometriotic tissues, along with its negative regulatory effect on fibrosis-related proteins TGFBR1/p-SMAD2/α-SMA/FN1 in vitro. It is important to note that, while our study provides compelling evidence supporting the crucial role of ubiquitination in endometriosis and the negative regulatory effect of TRIM33 on fibrosis, the specific regulatory mechanisms require further in-depth functional studies. This study contributes to a deeper understanding of endometriosis pathogenesis and highlights the potential of targeting ubiquitination pathways for therapeutic intervention in this debilitating condition.

ORGANISM(S): Homo Sapiens

SUBMITTER: Qionghua Chen

PROVIDER: PXD036497 | iProX | Tue Apr 09 00:00:00 BST 2024

REPOSITORIES: iProX

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Multi-omics integration highlights the role of ubiquitination in endometriosis fibrosis.

Yang Mengjie M Jiang Hong H Ding Xinyu X Zhang Lu L Zhang Huaying H Chen Jiahao J Li Lijun L He Xinqin X Huang Zhixiong Z Chen Qionghua Q

Journal of translational medicine 20240512 1

<h4>Background</h4>Endometriosis, characterized by the presence of active endometrial-like tissues outside the uterus, causes symptoms like dysmenorrhea and infertility due to the fibrosis of endometrial cells, which involves excessive deposition of extracellular matrix (ECM) proteins. Ubiquitination, an important post-transcriptional modification, regulates various biological processes in human diseases. However, its role in the fibrosis process in endometriosis remains unclear.<h4>Methods</h4> ...[more]

PMID: 38735939

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Project description:Huntington’s disease is caused by a polyglutamine repeat expansion at the N-terminus of the huntingtin protein which affects the function and folding of the protein, and results in intracellular protein aggregates. Here, we examined whether this mutation leads to altered ubiquitination of huntingtin and other proteins in both soluble and insoluble fractions of brain lysates of the Q175 knock-in Huntington disease mouse model and the Q20 wild-type mouse model. Ubiquitination sites are detected by identification of Gly-Gly (diGly) remnant motifs that remain on modified lysine residues after digestion. We identified K6, K9, K132, K804 and K837 as endogenous ubiquitination sites of soluble huntingtin, with wild-type huntingtin being mainly ubiquitinated at K132, K804 and K837. Mutant huntingtin protein levels were strongly reduced in the soluble fraction while K6 and K9 were mainly ubiquitinated. In the insoluble fraction increased levels of huntingtin K6 and K9 diGly sites were observed for mutant huntingtin as compared to wild type. Besides huntingtin, proteins with various roles, including membrane organization, transport, mRNA processing, gene transcription, translation, catabolic processes and oxidative phosphorylation, were differently expressed or ubiquitinated in wild-type and mutant huntingtin brain tissues. Correlating protein and diGly site fold-changes in the soluble fraction revealed that diGly site abundances of the majority of the proteins were not related to protein fold-changes, indicating that these proteins were differentially ubiquitinated in the Q175 mice. In contrast, both the fold-change of the protein level and diGly site level were increased for several proteins in the insoluble fraction, including ubiquitin, ubiquilin-2, sequestosome-1/p62 and myo5a. Our data sheds light on putative novel proteins involved in different cellular processes as well as their ubiquitination status in Huntington’s disease, which forms the basis for further mechanistic studies to understand the role of differential ubiquitination of huntingtin as well as ubiquitin-regulated processes in Huntington’s disease.

Project description:Translation elongation rates are regulated to ensure proper conformation and biological function of proteins. Translation of either non-stop mRNA or transcripts coding for poly-basic sequences induces ribosome stalling, and the arrest product is degraded by the ribosome-mediated quality control system (RQC). During this process, the stalled ribosome is dissociated into subunits, and the polypeptide is ubiquitinated by the E3 ubiquitin ligase Listerin on the 60S large ribosomal subunit (LSU) leading to subsequent proteasomal degradation. However, it is largely unknown how stalled ribosomes are recognized and dissociated into subunits. Here we report that ubiquitination of the ribosomal protein uS10 by the E3 ubiquitin ligase Hel2 is required for the production of the RQC substrate. RQC-trigger (RQT) factors, a RNA helicase-family protein Slh1/Rqt2, ubiquitin binding protein Cue3/Rqt3 and yKR023W/Rqt4, were also required for the primary steps of RQC, and associated with Hel2-ribosome complexes. Rqt2-4 factors were dispensable for the ubiquitination of uS10 by Hel2/Rqt1 and associated with ribosomes independent of the ubiquitination of uS10. However, the ubiquitin-binding activity of Rqt3 were crucial to trigger RQC. Cryo-electron microscopy (cryo-EM) analysis revealed that Hel2 bound ribosomes are in an rotated state containing hybrid state AP- and PE-tRNAs. Furthermore, ribosome profiling revealed that short footprints, hallmarks of hybrid state ribosomes18, were accumulated at tandem CGA rare codons at the beginning of the poly arginine stalling sequence and long footprints at subsequent codons, respectively. Short footprints at CGA codons were decreased in rqt1 mutant but drastically increased in uS10 mutants defective in the ubiquitination or rqt2 mutant. Collectively, our results demonstrate that Hel2 stabilizes ratcheted ribosomes leading to ubiquitination of uS10. Subsequently, Rqt2-4 factors target these hybrid state ribosomes specifically, allowing subsequent RQC reactions.

Dataset Information

Multi-Omics Integration Highlights the Role of Ubiquitination in Endometriosis Fibrosis

Publications

Multi-omics integration highlights the role of ubiquitination in endometriosis fibrosis.

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