Protein arginine deiminase 4 antagonizes methylglyoxal-induced histone glycation

Abstract

Protein arginine deiminase 4 (PAD4) facilitates the post-translational citrullination of the core histones H3 and H4. While the precise epigenetic function of this modification has not been resolved, it has been shown to associate with general chromatin decompaction and compete with arginine methylation. Recently, we found that histones are subjected to methylglyoxal (MGO)-induced glycation on nucleophilic side chains, particularly arginines, under metabolic stress conditions. These non-enzymatic adducts change chromatin architecture and the epigenetic landscape by competing with enzymatic modifications, as well as changing the overall biophysical properties of the fiber. Here, we report that PAD4 antagonizes histone MGO-glycation by protecting the reactive arginine sites, as well as by converting already-glycated arginine residues into citrulline. Moreover, we show that similar to the deglycase DJ-1, PAD4 is overexpressed and histone citrullination is upregulated in breast cancer tumors, suggesting an additional mechanistic link to PAD4's oncogenic properties.

Genomic GLO1 deletion modulates TXNIP expression, glucose metabolism, and redox homeostasis while accelerating human A375 malignant melanoma tumor growth

“…Cumulative evidence supports a role of GLO1 expression in tumorigenesis that may involve various mechanisms including alteration of cellular energy and redox homeostasis, defense against electrophilic carbonyl and chemotherapeutic stress, and epigenetic control of histone adduction and gene expression [ 8 , 9 , [11] , [12] , [13] , [14] , [15] , [16] ]. Specifically, an oncometabolic function of the glycolytic byproduct MG, regulated by the glyoxalase detoxification system, has been substantiated by numerous lines of investigation, and a double-edged, hormetic role of MG, serving pro-proliferative and tumorigenic functions at low concentrations while displaying cytotoxic, anti-proliferative, and tumor-suppressive activities at higher concentrations, has been demonstrated [ 6 , 8 , 11 , 13 , 16 , 24 , 64 ].…”

“…Cumulative evidence supports a crucial role of GLO1 expression in maintaining oncometabolic adaptations as observed in the context of tumor-associated aerobic glycolysis, commonly referred to as ‘the Warburg effect’, facilitating survival under hypoxic conditions and enabling escape from energy crisis and apoptosis [ [8] , [9] , [10] ]. Substantiating a role of GLO1 in metabolic reprogramming, cumulative research has focused on the emerging role of MG [and (R)-S-lactoylglutathione] as cellular oncometabolites, involved in tumorigenesis-associated proliferative control, redox dysregulation, epigenetic recoding, and regulation of EMT, cellular functions that have been attributed to posttranslational MG-adduction of specific target proteins including histones [ 8 , 9 , [11] , [12] , [13] , [14] , [15] , [16] ]. Importantly, numerous malignancies (including those of the breast, colon, liver, lung, prostate, skin, stomach, and thyroid) have now been associated with a causative role of GLO1 dysregulation, and beyond serving as a prognostic factor of patient survival, development of pharmacological and genetic strategies targeting cancer cells through GLO1 modulation has attracted significant attention [ 10 , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] ].…”

Mapping sites of carboxymethyllysine modification on proteins reveals its consequences for proteostasis and cell proliferation

“…For instance, K92 on histone H4, which became substantially more modified with CML during aging, has been reported to be also a target of acetylation and glutarylation, which are both involved in the regulation of chromatin structure and dynamics in response to DNA damage (Bao et al, 2019;Ye et al, 2005). Furthermore, global glycation of histone 3 has been shown to compete with acetylation and methylation thereby disrupting chromatin architecture (Zheng et al, 2019;Zheng et al, 2020). Thus, the age-dependent increase in CML modification of histone H4-K92 as seen in our study may contribute to alteration of chromatin and DNA damage responses in old tissues via interfering with other PTM.…”

“…Glycation of extracellular proteins such as hemoglobin HbA1c (Shapiro et al, 1980) or collagen (Avery and Bailey, 2005) is well described, but reports on glycation of intracellular proteins are still scarce. Examples of those are histones (Ansari et al, 2018;Baldensperger et al, 2020;Galligan et al, 2018;Guedes et al, 2011;Mir et al, 2014;Zheng et al, 2019;Zheng et al, 2020), mitochondrial proteins (Hamelin et al, 2007;Rosca et al, 2005;Wang et al, 2009), the 20S proteasome (Queisser et al, 2010), enzymes involved in energy production (Snow et al, 2007), small heat shock proteins (Oya-Ito et al, 2006;Schalkwijk et al, 2006;Sudnitsyna and Gusev, 2017) and the sodium channel Nav1.8 (Bierhaus et al, 2012). Glycation is increasingly seen as a driver of metabolic disease and aging, and it may elicit specific effects by targeting signaling proteins (Chaudhuri et al, 2018;Kold-Christensen and Johannsen, 2020).…”

“…The latter may play a role in the upregulation of defense systems, such as GLO1 and the ubiquitin-proteasome system (UPS), and may be involved in the hormetic effect of methylglyoxal (Ravichandran et al, 2018). In contrast to earlier assumptions of irreversible AGE formation, recent studies suggested the possibility of deglycation via DJ-1 or protein arginine deiminase 4 (Zheng et al, 2019;Zheng et al, 2020).…”