Evolutionary insights reveal a new role of peptidyl arginine deiminase 2 in transcription regulation
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PROVIDER: PRJNA1032907 | ENA |
REPOSITORIES: ENA
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Project description:Evolutionary insights reveal a new role of peptidyl arginine deiminase 2 in transcription regulationA systematic evolutionary analysis identified positively selected residues in the non-catalytic domain of PADI2. We established a link between the positive evolution of key residues in the PADI2 and their role in transcription. Specifically, we identified the structurally exposed loop encompassing the positively selected L162 in the PADI2 middle domain and its role in transcription and cellular proliferation. This loop contributes to the PADI2 interaction with the P-TEFb complex and cellular proliferation. Our results showcase the use of combining evolutionary and experimental approaches to dissect the dynamic of evolutionary processes.
2024-03-15 | GSE246420 | GEO
Project description:ObjectivesThe conversion of protein arginine residues to citrulline by calcium-dependent peptidyl arginine deiminases (PADs) has been implicated in the pathogenesis of several diseases, indicating that PADs are therapeutic targets. A recent study indicated that PAD4 regulates age-related organ fibrosis and dysfunction; however, the specific role of this PAD and its citrullination substrate remains unclear. We investigated whether pharmacological inhibition of PAD activity could affect the progression of fibrosis and restore heart function.MethodsCardiac hypertrophy was induced by chronic infusion of angiotensin (Ang) II. After 2 weeks of AngII infusion, a PAD inhibitor (Cl-amidine hydrochloride) or vehicle (saline) was injected every other day for the next 14 days together with the continued administration of AngII for a total of up to 28 days. Cardiac fibrosis and remodeling were evaluated by quantitative heart tissue histology, echocardiography, and mass spectrometry.ResultsA reverse AngII-induced effect was observed in PAD inhibitor-treated mice (n=6) compared with AngII vehicle-treated mice, as indicated by a significant reduction in the heart/body ratio (AngII: 6.51±0.8 mg/g vs. Cl-amidine: 5.27±0.6 mg/g), a reduction in fibrosis (AngII: 2.1-fold increased vs. Cl-amidine: 1.8-fold increased), and a reduction in left ventricular posterior wall diastole (LWVPd) (AngII: 1.1±0.04 vs. Cl-amidine: 0.78±0.02 mm). Label-free quantitative proteomics analysis of heart tissue indicated that proteins involved in fibrosis (e.g., periostin), cytoskeleton organization (e.g., transgelin), and remodeling (e.g., myosin light chain, carbonic anhydrase) were normalized by Cl-amidine treatment.ConclusionOur findings demonstrate that pharmacological inhibition of PAD may be an effective strategy to attenuate cardiac fibrosis.
| S-EPMC10408542 | biostudies-literature
Project description:Protein arginine deimination leading to the non-coded amino acid citrulline remains a key question in the field of post-translational modifications ever since its discovery by Rogers and Simmonds in 1958. Citrullination is catalyzed by a family of enzymes called peptidyl arginine deiminases (PADIs). Initially, increased citrullination was associated with autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, as well as other neurological disorders and multiple types of cancer. During the last decade, research efforts have focused on how citrullination contributes to disease pathogenesis by modulating epigenetic events, pluripotency, immunity and transcriptional regulation. However, our knowledge regarding the functional implications of citrullination remains quite limited, so we still do not completely understand its role in physiological and pathological conditions. Here, we review the recently discovered functions of PADI2-mediated citrullination of the C-terminal domain of RNA polymerase II in transcriptional regulation in breast cancer cells and the proposed mechanisms to reshape the transcription regulatory network that promotes cancer progression.
| S-EPMC7072959 | biostudies-literature
Project description:Peptidyl arginine deiminase-4 (PAD4) catalyzes the conversion of peptidylarginine residues to peptidylcitrulline. We have previously shown that kidney ischemia-reperfusion (I/R) injury increases renal proximal tubular PAD4 expression and activity. Furthermore, kidney PAD4 plays a critical role in ischemic acute kidney injury (AKI) by promoting renal tubular inflammation, neutrophil infiltration, and NF-?B activation. However, the mechanisms of PAD4-mediated renal tubular inflammation and NF-?B activation after I/R remain unclear. Here, we show that recombinant PAD4 preferentially citrullinates recombinant IKK? [also called NF-?B essential modulator (NEMO)] over recombinant IKK? or IKK?. Consistent with this finding, PAD4 citrullinated renal proximal tubular cell IKK? and promoted NF-?B activation via I?B? phosphorylation in vitro. NEMO inhibition with a selective NEMO-binding peptide attenuated PAD4-mediated proinflammatory cytokine mRNA induction in HK-2 cells. Moreover, NEMO inhibition did not affect proximal tubular cell survival, proliferation, or apoptosis, unlike global NF-?B inhibition. In vivo, NEMO-binding peptide treatment protected against ischemic AKI. Finally, NEMO-binding peptide attenuated recombinant PAD4-mediated exacerbation of ischemic AKI, renal tubular inflammation, and apoptosis. Taken together, our results show that PAD4 exacerbates ischemic AKI and inflammation by promoting renal tubular NF-?B activity and inflammation via NEMO citrullination. Targeting NEMO activation may serve as a potential therapy for this devastating clinical problem.
| S-EPMC6620589 | biostudies-literature
Project description:Peptidyl arginine deiminases (PADIs) catalyze protein citrullination, a post-translational conversion of arginine to citrulline. The most widely expressed member of this family, PADI2, regulates cellular processes that impact several diseases. We hypothesized that we could gain new insights into PADI2 function through a systematic evolutionary and structural analysis. Here, we identify 20 positively selected PADI2 residues, 16 of which are structurally exposed and maintain PADI2 interactions with cognate proteins. Many of these selected residues reside in non-catalytic regions of PADI2. We validate the importance of a prominent loop in the middle domain that encompasses PADI2 L162, a residue under positive selection. This site is essential for interaction with the transcription elongation factor (P-TEFb) and mediates the active transcription of the oncogenes c-MYC, and CCNB1, as well as impacting cellular proliferation. These insights could be key to understanding and addressing the role of the PADI2 c-MYC axis in cancer progression.
| S-EPMC11016909 | biostudies-literature
Project description:Transcriptional profiling of MDA-MB-231 and its ρ0 cells (lacking mtDNA) after 48h arginine depletion by arginine deiminase (ADI).
| PRJNA408268 | ENA
Project description:Protein citrullination is carried out by peptidylarginine deiminase type 4 (PAD4) enzyme. As a consequence of this process, post-translationally modified proteins are formed that become antigens for anti-citrullinated protein antibodies (ACPA). The study aimed at identifying whether the PADI4 gene is subject to epigenetic regulation through methylation of its promoter region, whether the degree of methylation differs in healthy individuals vs. rheumatoid arthritis (RA) patients and changes in correlation with ACPA, anti-PAD4 and disease activity. A total of 125 RA patients and 30 healthy controls were enrolled. Quantitative real-time methylation-specific PCR was used to analyze the methylation status. ACPA and anti-PAD4 antibodies were determined in serum by enzyme-linked immunosorbent immunoassay. The differences were observed in the degree of PADI4 gene promoter methylation between RA patients and HC, along with an upward trend for the methylation in RA, which was inversely proportional to the disease activity. A weak or modest negative correlation between the degree of PADI4 gene methylation and anti-PAD4, disease activity score (DAS28) and ACPA level has been found. The elevated methylation is associated with lower disease activity, lower levels of ACPA and aPAD4. The methylation degree in this area is growing up during effective treatment and might play a role in the RA pathophysiology and therefore could be a future therapeutic target.
| S-EPMC7408948 | biostudies-literature
Project description:The Ca2+-dependent enzyme peptidyl-arginine deiminase type III (PAD3) catalyses the deimination of arginine residues to form citrulline residues in proteins such as keratin, filaggrin and trichohyalin. This is an important post-translation modification that is required for normal hair and skin formation in follicles and keratocytes. The structure of apo human PAD3 was determined by X-ray crystallography to a resolution of 2.8 Å. The structure of PAD3 revealed a similar overall architecture to other PAD isoforms: the N-terminal and middle domains of PAD3 show sequence and structural variety, whereas the sequence and structure of the C-terminal catalytic domain is highly conserved. Structural analysis indicates that PAD3 is a dimer in solution, as is also the case for the PAD2 and PAD4 isoforms but not the PAD1 isoform.
| S-EPMC8488854 | biostudies-literature
Project description:Peptidylarginine deiminase (PADI) 2 catalyzes the posttranslational conversion of peptidyl-arginine to peptidyl-citrulline, a process called citrullination. However, the exact function of PADI2 in bone development and bone homeostasis remains unknown. In this study, we found that Padi2 deficiency lead to loss of bone mass and cleidocranial dysplasia (CCD)-like phenotype with delayed calvarial ossification and clavicular hypoplasia due to impaired osteoblast differentiation. Mechanistically, Padi2 depletion drastically reduced RUNX2 protein level and PADI2 stabilized RUNX2 from ubiquitin-proteasomal degradation. Furthermore, we identified a new modification at RUNX2, citrullination of arginine and its conversion to citrulline by PADI2. PADI2 citrullinates RUNX2 via a direct physical interaction and the citrullination sites at RUNX2 by PADI2 were identified by high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Interestingly, in mouse RUNX2 isoform 1 (528 a.a), loss of R381, a citrullination site by PADI2, drastically reduced RUNX2 protein levels, indicating that the citrullination of RUNX2 by PADI2 is required for the maintenance of RUNX2 protein stability. Collectively, our study demonstrates that PADI2-mediated citrullination play key roles in bone formation and bone homeostasis. Also, CCD may result from functional defects of RUNX2 by Padi2 deficiency. These insights into the role of PADI2 in postnatal bone formation and homeostasis and CCD pathogenesis may assist in the development of new therapies for bone diseases including CCD.
2023-10-24 | PXD040179 | Pride
Project description:In this study, the effect of arginine deprivation on global gene expression in MDA-MB-231 and its ρ0 cells were examined. MDA-MB-231 ρ0 cells lack mitochondrial DNA and therefore have impaired OXPHOS function. Both parental and ρ0 cells were cultured in complete or arginine depleted medium for 48 hours. Comparative transcriptome analysis of both cell lines in complete growth medium versus arginine depleted medium were performed.
2018-11-02 | GSE104105 | GEO