The UFM1 System Alleviated Fatty Acid Oxidation and Chondrocyte Senescence via the UFMylation of CAVIN1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1101409 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28715536_1.fastq.gz | Fastqsanger.gz | |||
| SRR28715536_2.fastq.gz | Fastqsanger.gz | |||
| SRR28715537_1.fastq.gz | Fastqsanger.gz | |||
| SRR28715537_2.fastq.gz | Fastqsanger.gz | |||
| SRR28715538_1.fastq.gz | Fastqsanger.gz |
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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 senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide siRNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is a substrate of the DDR kinase ATM and contributes to an increase in the number of mitochondrial cristae upon DNA damage. Stable isotope labeling metabolomics indicated that this increase in cristae enhances the oxidation of fatty acids to acetyl-CoA. Notably, pharmacological activation of fatty acid oxidation alone induced senescence both in vitro and in vivo. Our findings suggest that mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.
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Project description:Sirt6 attenuates chondrocyte senescence and osteoarthritis progression
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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.
2018-12-11 | GSE123539 | GEO
Project description:Cartilage aging is a quintessential feature of knee osteoarthritis, and extracellular matrix (ECM) stiffening is a typical feature of cartilage aging. However, the mechanism of ECM stiffening to influence chondrocytes and downstream molecules is still poorly understood. Here, we mimicked the physiological and pathological stiffness of human cartilage by using polydimethylsiloxane-based substrates. We show that the epigenetic regulation of Parkin by histone deacetylase 3 (HDAC3) represents a new mechanosensitive mechanism by which the stiff matrix affects the physiology of chondrocytes. We found that ECM stiffening could accelerate the senescence of cultured chondrocytes in vitro, and also found that stiff ECM downregulated HDAC3, drove Parkin acetylation to activate excessive mitophagy, and accelerated chondrocyte senescence and osteoarthritis in mice. In contrast, intra-articular injection of adeno-associated virus expressing HDAC3 restored the young phenotype of aged chondrocytes stimulated by ECM stiffening and alleviated osteoarthritis in mice. Our findings indicate that changes in the mechanical properties of ECM initiate pathogenic mechanotransduction signals, promote the acetylation of Parkin and hyperactivate mitophagy, and damage the health of chondrocytes. These findings may provide new insights into how the mechanical properties of ECM regulate chondrocytes.
2024-06-16 | PXD046993 | Pride
Project description:It has been found that fat oxidation is reduced in the skeletal muscle of obese humans. This study aims to identify the mRNA of proteins involved in fat oxidation that may be reduced in obese and morbidly obese individuals. Information gathered will help in understanding how obesity contributes to cardiovascular disease via insulin resistance. Keywords: other
2003-07-16 | GSE474 | GEO
Project description:DNA damage-activated mitochondrial fatty acid oxidation drives senescence
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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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Project description:Sirt6 attenuates chondrocyte senescence and osteoarthritis progression
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Project description:UFMylation, is a Ubiquitin-like modification occurring on RPL26, a ribosomal subunit, upon ribosome stalling at the ER membrane. This modification is achieved by a pool of enzymes commonly referred to as E1-activating, E2-conjugating and E3-ligase enzymes. The UFM1 E3 ligase comprises of three proteins: UFL1, UFBP1 and CDK5RAP3, referred to as UFM1 Ribosome E3 Ligase (UREL) complex. While UFL1 and UFBP1 are sufficient for E3 ligase activity in vitro, CDK5RAP3 is indispensable for ribosome UFMylation in vivo. In this work, we characterize in vitro UFMylation reaction of purified 60S ribosomes in the presence and absence of CDK5RAP3 using LC-MS/MS. Specifically, we analyse sites of UFMylation, linkage type and quantify monoUFMylation and diUFMylation on RPL26. Interestingly, we find UFMylation to occur on a specific lysine residue, K134, in the presence of UFL1/UFBP1 alone and in complex with CDK5RAP3. In addition, we also provide quantitative information on relative abundances of RPL26 mono- and di-UFMylation under these conditions.
2024-03-22 | PXD046991 | Pride