Highlighting the versatility of the citrullination process

Sarnik, Joanna; Makowska, Joanna

doi:10.1016/j.imbio.2022.152233

Cited by 4 publications

(4 citation statements)

References 267 publications

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“…Next, we assessed cervical cancer vs. NILM for protein expression levels of PADs 2 and 4, the two PAD isozymes most broadly expressed in human cancer ( Yuzhalin, 2019 ; Sarnik and Makowska, 2022 ). In NILM, PAD4 expression was limited to the nuclei in basal and parabasal layers of the squamous epithelium and in sparse stromal and inflammatory cells within the stromal compartment ( Figure 1C ).…”

Section: Resultsmentioning

confidence: 99%

PAD-mediated citrullination is a novel candidate diagnostic marker and druggable target for HPV-associated cervical cancer

Albano,

Biolatti,

Mazibrada

et al. 2024

Front. Cell. Infect. Microbiol.

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Citrullination is an emerging post-translational modification catalyzed by peptidyl-arginine deiminases (PADs) that convert peptidyl-arginine into peptidyl-citrulline. In humans, the PAD family consists of five isozymes (PADs 1-4, 6) involved in multiple diseases, including cancer. Given that high-risk (hr) human papillomaviruses (HPVs) are the etiological agents of cervical cancer, in this study, we sought to determine whether PAD-mediated protein citrullination would play a functional role in the HPV-driven transformation of epithelial cells. Here we show that both total protein citrullination and PAD4 expression levels are significantly associated with cervical cancer progression. Specifically, epithelial immunostaining for PAD4 revealed an increasingly higher histoscore from low-grade (CIN1) to high-grade (CIN2, CIN3) cervical intraepithelial neoplasia, and invasive squamous cell carcinoma (SCC) lesions, raising the attractive possibility that PAD4 may be used as tumor staging markers. Furthermore, taking advantage of the epidermoid cervical cancer cell line CaSki, which harbors multiple copies of the integrated HPV16 genome, we show that the expression of E6 and E7 HPV oncoproteins is impaired by treatment with the pharmacological pan-PAD inhibitor BB-Cl-amidine. Consistently, p53 and p21, two targets of HPV oncoproteins, are upregulated by the PAD inhibitor, which undergoes cell growth arrest and apoptosis. Altogether, these findings highlight a novel mechanism by which hrHPVs alter host regulatory pathways involved in cell cycle and survival to gain viral fitness, raising the possibility that PADs may represent an attractive target for developing novel host-targeting antivirals effective in preventing cervical cancer progression.

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Section: Resultsmentioning

confidence: 99%

PAD-mediated citrullination is a novel candidate diagnostic marker and druggable target for HPV-associated cervical cancer

Albano,

Biolatti,

Mazibrada

et al. 2024

Front. Cell. Infect. Microbiol.

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“…The guanidinium group also losses two hydrogen-bond donors but obtains two hydrogen-bond acceptor sites . Protein citrullination regulates a variety of cellular processes, including gene expression, cell signaling, metabolism, and apoptosis. , It is associated with a variety of human diseases, including cancers, inflammatory and autoimmune disorders, cardiovascular diseases, and neurodegeneration diseases . Citrullination is catalyzed by peptidyl arginine deiminases (PADs) .…”

Section: Arginine Modificationsmentioning

confidence: 99%

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

Gan,

Fan

2024

Chem. Rev.

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Post-translational modifications (PTMs) endow proteins with new properties to respond to environmental changes or growth needs. With the development of advanced proteomics techniques, hundreds of distinct types of PTMs have been observed in a wide range of proteins from bacteria, archaea, and eukarya. To identify the roles of these PTMs, scientists have applied various approaches. However, high dynamics, low stoichiometry, and crosstalk between PTMs make it almost impossible to obtain homogeneously modified proteins for characterization of the site-specific effect of individual PTM on target proteins. To solve this problem, the genetic code expansion (GCE) strategy has been introduced into the field of PTM studies. Instead of modifying proteins after translation, GCE incorporates modified amino acids into proteins during translation, thus generating site-specifically modified proteins at target positions. In this review, we summarize the development of GCE systems for orthogonal translation for site-specific installation of PTMs.

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“…Anti-citrullinated protein antibodies (ACPA) are directed against posttranslational modified, citrullinated proteins. The presence of ACPA precedes the clinical onset of RA, and the level of ACPA correlates with the patient's prognosis [8]. CD40 is a transmembrane protein expressed on antigen-presenting cells, which binds to CD40 ligand expressed on lymphocytes T. Expression of CD40 is crucial for a threshold of activation of lymphocytes T and further steps of the immune response leading to autoantibody production and activation of macrophages [9,10].…”

Section: Introductionmentioning

confidence: 99%

SNP in PTPN22, PADI4, and STAT4 but Not TRAF1 and CD40 Increase the Risk of Rheumatoid Arthritis in Polish Population

Budlewski

Sarnik

Galita

et al. 2023

IJMS

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Single nucleotide polymorphisms in non-HLA genes are involved in the development of rheumatoid arthritis (RA). SNPS in genes: PADI4 (rs2240340), STAT4 (rs7574865), CD40 (rs4810485), PTPN22 (rs2476601), and TRAF1 (rs3761847) have been described as risk factors for the development of autoimmune diseases, including RA. This study aimed to assess the prevalence of polymorphisms of these genes in the Polish population of patients with rheumatoid arthritis as compared to healthy controls. 324 subjects were included in the study: 153 healthy subjects and 181 patients from the Department of Rheumatology, Medical University of Lodz who fulfilled the criteria of rheumatoid arthritis diagnosis. Genotypes were determined by Taqman SNP Genotyping Assay. rs2476601 (G/A, OR = 2.16, CI = 1.27–3.66; A/A, OR = 10.35, CI = 1.27–84.21), rs2240340 (C/T, OR = 4.35, CI = 2.55–7.42; T/T, OR = 2.80, CI = 1.43–4.10) and rs7574865 (G/T, OR = 1.97, CI = 1.21–3.21; T/T, OR = 3.33, CI = 1.01–11.02) were associated with RA in the Polish population. Rs4810485 was also associated with RA, however after Bonferroni’s correction was statistically insignificant. We also found an association between minor alleles of rs2476601, rs2240340, and rs7574865 and RA (OR = 2.32, CI = 1.47–3.66; OR = 2.335, CI = 1.64–3.31; OR = 1.88, CI = 1.27–2.79, respectively). Multilocus analysis revealed an association between CGGGT and rare (below 0.02 frequency) haplotypes (OR = 12.28, CI = 2.65–56.91; OR = 3.23, CI = 1.63–6.39). In the Polish population, polymorphisms of the PADI4, PTPN22, and STAT4 genes have been detected, which are also known risk factors for RA in various other populations.

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Highlighting the versatility of the citrullination process

Cited by 4 publications

References 267 publications

PAD-mediated citrullination is a novel candidate diagnostic marker and druggable target for HPV-associated cervical cancer

PAD-mediated citrullination is a novel candidate diagnostic marker and druggable target for HPV-associated cervical cancer

Orthogonal Translation for Site-Specific Installation of Post-translational Modifications

SNP in PTPN22, PADI4, and STAT4 but Not TRAF1 and CD40 Increase the Risk of Rheumatoid Arthritis in Polish Population

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