Peptidylarginine deiminase and protein citrullination in prion diseases

Jang, Byungki; Ishigami, Akihito; Maruyama, Naoki; Carp, Richard I.; Kim, Yong‐Sun; Choi, Eun‐Kyoung

doi:10.4161/pri.22380

Cited by 50 publications

(40 citation statements)

References 58 publications

(81 reference statements)

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“…Citrullination or deamination is the posttranslational modification of peptidyl arginine to peptidyl citrulline residue catalyzed by the PAD family of enzymes (4,15,42). Of the five PAD subtypes in humans and rodents, PAD4 activity has received significant scientific and clinical interest due to its active role in innate immunity and autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, ulcerative colitis, and lupus (2,4).…”

Section: Discussionmentioning

confidence: 99%

“…PAD4 requires dimerization and Ca 2ϩ -mediated conformational changes to promote the deamination process (4,15,42). PAD4 is known to be activated by the rise in intracellular Ca 2ϩ as well as by ROS and proinflammatory cytokines (e.g., TNF-␣), chemokines (e.g., IL-8), and Toll-like receptor ligands (e.g., lipopolysaccharides) (37).…”

Section: Discussionmentioning

confidence: 99%

“…Posttranslational protein citrullination leads to drastic changes on protein charge, structure, and function (12,15,42). Of the five known subtypes of PAD (PAD1, PAD2, PAD3, PAD4, and PAD6), PAD4 is the only PAD enzyme localized in the nucleus and is the only PAD protein detected in the kidney (39,41).…”

mentioning

confidence: 99%

“…Of the five known subtypes of PAD (PAD1, PAD2, PAD3, PAD4, and PAD6), PAD4 is the only PAD enzyme localized in the nucleus and is the only PAD protein detected in the kidney (39,41). PAD4-mediated posttranslational protein citrullination has been implicated in several inflammatory autoimmune diseases, including colitis, lupus, rheumatoid arthritis, and multiple sclerosis (2,15,27). Furthermore, PAD4-mediated citrullination of histones is critical for neutrophil extracellular trap formation after bacterial infection or the development of deep vein thrombosis (28,29).…”

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confidence: 99%

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Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury

Ham

Rabadi

Kim

et al. 2014

American Journal of Physiology-Renal Physiology

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Peptidyl arginine deiminase (PAD)4 is a nuclear enzyme that catalyzes the posttranslational conversion of arginine residues to citrulline. Posttranslational protein citrullination has been implicated in several inflammatory autoimmune diseases, including rheumatoid arthritis, colitis, and multiple sclerosis. Here, we tested the hypothesis that PAD4 contributes to ischemic acute kidney injury (AKI) by exacerbating the inflammatory response after renal ischemia-reperfusion (I/R). Renal I/R injury in mice increased PAD4 activity as well as PAD4 expression in the mouse kidney. After 30 min of renal I/R, vehicle-treated mice developed severe AKI with large increases in plasma creatinine. In contrast, mice pretreated with PAD4 inhibitors (2-chloroamidine or streptonigrin) had significantly reduced renal I/R injury. Further supporting a critical role for PAD4 in generating ischemic AKI, mice pretreated with recombinant human PAD4 (rPAD4) protein and subjected to mild (20 min) renal I/R developed exacerbated ischemic AKI. Consistent with the hypothesis that PAD4 regulates renal tubular inflammation after I/R, mice treated with a PAD4 inhibitor had significantly reduced renal neutrophil chemotactic cytokine (macrophage inflammatory protein-2 and keratinocyte-derived cytokine) expression and had decreased neutrophil infiltration. Furthermore, mice treated with rPAD4 had significantly increased renal tubular macrophage inflammatory protein-2 and keratinocyte-derived cytokine expression as well as increased neutrophil infiltration and necrosis. Finally, cultured mouse kidney proximal tubules treated with rPAD4 had significantly increased proinflammatory chemokine expression compared with vehicle-treated cells. Taken together, our results suggest that PAD4 plays a critical role in renal I/R injury by increasing renal tubular inflammatory responses and neutrophil infiltration after renal I/R.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury

Ham

Rabadi

Kim

et al. 2014

American Journal of Physiology-Renal Physiology

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“…Over expression of PADs and protein citrullination are abnormal features of neurodegeneration and inflammatory diseases [66] and have actually been proposed as a possible cause of AD [67]. During neurodegenerative processes, it has been hypothesized that a higher concentration of Ca ++ activates citrullination [15] but, P. gingivalis LPS and intact citrulline constitute potential contributory factors [68].…”

Section: Introductionmentioning

confidence: 99%

Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and Alzheimer’s disease

Olsen

Singhrao

Potempa

2018

Journal of Oral Microbiology

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Periodontitis, rheumatoid arthritis (RA), atherosclerosis (AS), and Alzheimer’s disease (AD) are examples of complex human diseases with chronic inflammatory components in their etiologies. The initial trigger of inflammation that progresses to these diseases remains unresolved. Porphyromonas gingivalis is unique in its ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and consequently offers a plausible and exclusive link to these diseases through enzymatic conversion of arginine to citrulline. Citrullination is a post-translational enzymatic modification of arginine residues in proteins formed as part of normal physiological processes. However, PPAD has the potential to modify self (bacterial) and host proteins by deimination of arginine amino acid residues, preferentially at the C-terminus. Migration of P. gingivalis and/or its secreted PPAD into the bloodstream opens up the possibility that this enzyme will citrullinate proteins at disparate body sites. Citrullination is associated with the pathogenesis of multifactorial diseases such as RA and AD, which have an elusive external perpetrator as they show epidemiological associations with periodontitis. Therefore, PPAD deserves some prominence as an external antigen, in at least, a subset of RA and AD cases, with as yet unidentified, immune/genetic vulnerabilities.

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Association Between Brain Gene Expression, DNA Methylation, and Alteration of Ex Vivo Magnetic Resonance Imaging Transverse Relaxation in Late-Life Cognitive Decline

Dawe

Boyle

et al. 2017

JAMA Neurol

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vivo magnetic resonance imaging transverse relaxation is associated with late-life cognitive decline even after controlling for common neuropathologic conditions. However, the underlying neurobiology of this association is unknown.OBJECTIVE To investigate the association between brain gene expression, DNA methylation, and alteration of magnetic resonance imaging transverse relaxation in late-life cognitive decline.DESIGN, SETTING, AND PARTICIPANTS Data came from 2 community-based longitudinal cohort studies of aging and dementia, the Religious Orders Study, which began in 1993, and the Rush Memory and Aging Project, which began in 1997. All participants agreed to undergo annual clinical evaluations and to donate their brains after death. By October 24, 2016, a total of 1358 individuals had died and had brain autopsies that were approved by board-certified neuropathologists. Of those, 552 had undergone ex vivo imaging. The gene expression analysis was limited to 174 individuals with both imaging and brain RNA sequencing data. The DNA methylation analysis was limited to 225 individuals with both imaging and brain methylation data. MAIN OUTCOMES AND MEASURESMaps of ex vivo magnetic resonance imaging transverse relaxation were generated using fast spin echo imaging. The target was a composite measure of the transverse relaxation rate (R 2 ) that was associated with cognitive decline after controlling for common neuropathologic conditions. Next-generation RNA sequencing and DNA methylation data were generated using frozen tissue from the dorsolateral prefrontal cortex. Genome-wide association analysis was used to investigate gene expression and, separately, DNA methylation for signals associated with the R 2 measure. RESULTSOf the 552 individuals with ex vivo imaging data, 394 were women and 158 were men, and the mean (SD) age at death was 90.4 (6.0) years. Four co-expressed genes (PADI2 [Ensembl ENSG00000117115], ZNF385A [Ensembl ENSG00000161642], PSD2 [Ensembl ENSG00000146005], and A2ML1 [Ensembl ENSG00000166535]) were identified, of which higher expressions were associated with slower R 2 . The association of R 2 with cognitive decline was attenuated when the gene expression signals were added to the model, such that the mean (SE) coefficient of association was reduced from 0.028 (0.008) (P < .001) to 0.019 (0.009) (P = .03). The DNA methylation scan did not detect a genome-wide significant signal, but it revealed an anticorrelation between R 2 and DNA methylation in many of the cytosine-guanine dinucleotides.CONCLUSIONS AND RELEVANCE Brain gene expression and DNA methylation dysregulations are implicated in the alteration of brain tissue properties associated with late-life cognitive decline above and beyond the influence of common neuropathologic conditions.

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Peptidylarginine deiminase and protein citrullination in prion diseases

Cited by 50 publications

References 58 publications

Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury

Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury

Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and Alzheimer’s disease

Association Between Brain Gene Expression, DNA Methylation, and Alteration of Ex Vivo Magnetic Resonance Imaging Transverse Relaxation in Late-Life Cognitive Decline

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