UFMylation maintains YAP stability to promote vascular endothelial cell senescence
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1143423 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30113261_1.fastq.gz | Fastqsanger.gz | |||
| SRR30113261_2.fastq.gz | Fastqsanger.gz | |||
| SRR30113262_1.fastq.gz | Fastqsanger.gz | |||
| SRR30113262_2.fastq.gz | Fastqsanger.gz | |||
| SRR30113263_1.fastq.gz | Fastqsanger.gz |
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Project description:Endothelial cell senescence is an accomplice for vascular aging, which leads to cardiovascular diseases (CVD). Evidences showed that Hippo- Yes-associated protein (YAP) signaling pathway plays an essential role in aging-associated CVD. However, the exact role of YAP protein in endothelial cell senescence remains not fully clear. Here, we reported that YAP was elevated in senescent human umbilical vein endothelial cells (HUVECs) and inhibition of YAP by either specific siRNAs or inhibitor Verteporfin could attenuate HUVECs senescence. In contrast, overexpression of YAP induces cell senescence. Besides, we found that UFMylation activity and YAP were both elevated in senescent cells. Mechanistically, we found that UFMylation, a newly identified ubiquitin-like modification with essential biological functions, maintains the stability of YAP and further found that YAP is a substrate for UFMylation. Importantly, we found that compound 8.5, an inhibitor of E1 of UFMylation, can attenuate cell senescence with reduced YAP protein and alleviate vascular aging and improve cardiac function in aged mice. Therefore, compound 8.5 may be a potential small molecule for delaying vascular aging. Together, our finding provides molecular mechanism by which UFMylation maintains YAP stability and exerts an important role in promoting cell senescence, and identified that a previously unrecognized UFMylation is a potential therapeutic target for anti-aging.
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Project description:Osteoarthritis (OA) is a widespread age-related joint disease caused by the gradual loss of chondrocyte function along with age. Here, we found that UFMylation modification was lower-leveled in senescent cartilage, mediated chondrocyte senescence and OA phenotypes through targeting CAVIN1, which acted as a stimulator in chondrocyte senescence, mainly through promoting CPT1 expression and activating fatty acid β-oxidation (FAO). Physiologically, FAO was at a very low level in chondrocytes, while the anomalous activation of FAO accelerated chondrocyte senescence. UFMylation of CAVIN1 promoted its binding with TRIP12, leading to ubiquitination degradation. Therefore, UFMylation played a pivotal role in post-translationally modification of CAVIN1. Polymeric micellar nanoparticles (NPs) conjugated with UFM1 improved the stability of UFM1 recombinant protein (UFM1-rp), and extended the retention time of UFM1-rp in the mouse joint cavity. The administration of UFM1 into mouse joints using an advanced NP delivery system is effective in attenuating age-related pathogenesis. Therefore, we uncovered a previously unknown mechanism, UFM1-CAVIN1-CPT1 axis, in the protection of OA progression and constructed a new drug for OA treatment, and have provided important preliminary evidence toward the translation of our findings into clinical usage.
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Project description:Cellular homeostasis is tightly linked to proliferation ensuring that only healthy cells divide. Homeostasis-sensing pathways including mTOR and integrated stress response (ISR) employ phosphorylation to regulate translation initiation and consequently cell cycle progression. Whether ubiquitin or ubiquitin-like molecules impact on translation and proliferation as part of existing or novel pathways is unknown. Here, we combine cell cycle screening, mass spectrometry and ribosome profiling to elucidate the molecular mechanism by which UFMylation, the modification of proteins with ubiquitin-fold modifier 1 molecules, controls translational homeostasis and cell cycle progression. Perturbation of UFMylation prevents eIF4F translation initiation complex assembly and recruitment of the ribosome. The ensuing global translational shutdown is sensed by cyclin D1 and halts the cell cycle independently of canonical ISR and mTOR signaling. Our findings establish UFMylation as a key regulator of translation that employs the principle of conserved cellular sensing mechanisms to couple translational homeostasis to cell cycle progression.
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Project description:Sox2 is required to maintain osteosarcoma cell tumor initiation.Knockdown of Sox2 leads tpo loss of tumorigenic properties. To examine gene expression changes upon Sox2 knockdown, we performed microarray analysis on mouse osteosarcoma cells expressing scrambled or Sox2shRNA. We found that genes upregulated upon Sox2 knockdown included osteoblast diffrentiation genes and genes down regulated included cell cycle and RNA processing genes as well as YAP-TEAD target genes. The Hippo pathway has a profound tumor suppressive role in cancer by restraining the strong growth-promoting function of YAP. We have previously shown that the stem cell transcription factor Sox2 maintains the tumorigenicity of osteosarcoma cancer stem cells (CSCs). In this report, we describe that Sox2 maintains stemness by antagonizing the Hippo pathway via direct repression of Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), thereby leading to exaggerated YAP function. YAP is potently oncogenic in osteosarcoma and its depletion sharply reduces the tumorigenic CSC fraction. Low Nf2, low WWC1, and high YAP expression mark the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. This Sox2-Hippo axis is conserved and also operates in other Sox2-dependent cancers such as glioblastomas. We propose that disruption of YAP transcriptional activity reduces CSCs and could be a therapeutic strategy for Sox2- dependent tumors. Gene expression of 482 mouse lines mOS482 were analyzed by microarray. 3 replicates each of scrambled and Sox2shRNA were processed and hybridized
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Project description:UFM1 is a small, metazoan-specific, ubiquitin-like protein modifier that is essential for embryonic development. Although loss-of-function mutations in UFM1 conjugation are linked to ER stress, neither the biological function nor the relevant cellular targets of this protein modifier are known. Here we show that a largely uncharacterized ribosomal protein, RPL26, is the principal target of UFM1 conjugation. RPL26 UFMylation and deUFMylation is catalyzed by enzyme complexes tethered to the cytoplasmic surface of the ER and UFMylated RPL26 is highly enriched on ER membrane-bound ribosomes and polysomes. Biochemical analysis and structural modeling establish that UFMylated RPL26 and the UFMylation machinery are in close proximity to the SEC61 translocon, suggesting that this modification plays a direct role in cotranslational protein translocation into the ER. These data suggest that UFMylation is a ribosomal modification specialized to facilitate metazoan-specific protein biogenesis at the ER.
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Project description:The Tumor Suppressor Hic1 Maintains Chromosomal Stability Independent of Tp53
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Project description:Ribosomal DNA (rDNA) arrays are highly repetitive regions of the genome which encode essential genes required to produce ribosomes. DNA double-stranded breaks (DSBs) generated within rDNA genes elicit a unique cellular response involving robust transcriptional silencing and nucleolar reorganization into ‘cap’ structures at the nucleolar periphery. This process is coordinated by the nucleolar scaffolding protein TCOF1, which functions to recruit the DNA repair proteins NBS1 and TOPBP1 that activate the ATM and ATR kinases, resulting in ribosomal RNA (rRNA) transcriptional silencing and nucleolar segregation. However, the DNA damage and repair response at rDNA arrays remains incompletely understood. Here, we investigate the cellular response to rDNA DSBs using proteomics and genetic CRISPR-Cas9 screening. We show that the protein UFMylation pathway and the HUSH complex are important for cell viability and survival in response to rDNA DSBs, and that the E3 UFM1-ligase UFL1 and its heterodimer DDRGK1 are associated with TCOF1 at nucleolar caps. Loss of UFL1 leads to impaired ATM activation, reduced rRNA transcriptional silencing, and an overall reduction in nucleolar segregation. We identified ATM, UNC45A and SMC6 as UFMylated proteins, in which UFMylation may facilitate ATM activation and segregation of damaged rDNA to the nucleolar periphery. Altogether, our findings provide the first evidence for a role for UFMylation in rDNA DSB repair.
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