RESUMEN
Increased presence of IL-22+ cells in the skin is a characteristic finding in skin barrier defects, such as psoriasis and atopic dermatitis. However, mechanistic insight into effects of IL-22 on epidermal functioning is yet to be elucidated. One crucial step during epidermal differentiation is deimination or citrullination. Here, we show reduced levels of peptidylarginine deiminase 1, an enzyme that converts peptidylarginine into citrulline in lesional psoriatic skin. IL-22 signaling through the IL-22 receptor complex was found to suppress expression of peptidylarginine deiminase 1 in epidermal keratinocytes. Subsequently, total peptidylarginine deiminase activity and extent of protein deimination in keratinocytes treated with IL-22 were reduced together with a significant decrease in deimination of keratin 1 and FLG, both important for epidermal differentiation. Vitamin D and acitretin partly restored the peptidylarginine deiminase 1 defect caused by IL-22. Collectively, we show that IL-22 downregulates deimination, thus identifying a potential target for treatment of skin barrier defects.
Asunto(s)
Epidermis/patología , Interleucinas/metabolismo , Arginina Deiminasa Proteína-Tipo 1/genética , Psoriasis/genética , Acitretina/farmacología , Acitretina/uso terapéutico , Biopsia , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular , Citrulinación/efectos de los fármacos , Citrulinación/genética , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/genética , Dermatitis Atópica/patología , Regulación hacia Abajo , Epidermis/efectos de los fármacos , Epidermis/enzimología , Proteínas Filagrina/metabolismo , Humanos , Queratina-1/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/enzimología , Queratinocitos/patología , Cultivo Primario de Células , Arginina Deiminasa Proteína-Tipo 1/metabolismo , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Vitamina D/farmacología , Vitamina D/uso terapéutico , Interleucina-22RESUMEN
Chromodomain helicase DNA binding protein 4 (CHD4) is an ATPase subunit of the Nucleosome Remodelling and Deacetylation (NuRD) complex that regulates gene expression. CHD4 is essential for growth of multiple patient derived melanoma xenografts and for breast cancer. Here we show that CHD4 regulates expression of PADI1 (Protein Arginine Deiminase 1) and PADI3 in multiple cancer cell types modulating citrullination of arginine residues of the allosterically-regulated glycolytic enzyme pyruvate kinase M2 (PKM2). Citrullination of PKM2 R106 reprogrammes cross-talk between PKM2 ligands lowering its sensitivity to the inhibitors Tryptophan, Alanine and Phenylalanine and promoting activation by Serine. Citrullination thus bypasses normal physiological regulation by low Serine levels to promote excessive glycolysis and reduced cell proliferation. We further show that PADI1 and PADI3 expression is up-regulated by hypoxia where PKM2 citrullination contributes to increased glycolysis. We provide insight as to how conversion of arginines to citrulline impacts key interactions within PKM2 that act in concert to reprogramme its activity as an additional mechanism regulating this important enzyme.
Asunto(s)
Proliferación Celular/fisiología , Citrulinación/fisiología , Glucólisis/fisiología , Neoplasias/metabolismo , Arginina Deiminasa Proteína-Tipo 1/metabolismo , Arginina Deiminasa Proteína-Tipo 3/metabolismo , Piruvato Quinasa/metabolismo , Regulación Alostérica , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Humanos , Melanoma , Proteínas de la Membrana , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2 , Neoplasias/genética , Arginina Deiminasa Proteína-Tipo 1/genética , Arginina Deiminasa Proteína-Tipo 3/genética , Hormonas Tiroideas , Regulación hacia Arriba , Proteínas de Unión a Hormona TiroideRESUMEN
Frontier evidence suggests that dysregulation of long noncoding RNAs (lncRNA) is ubiquitous in all human tumors, indicating that lncRNAs might have essential roles in tumorigenesis. Therefore, an in-depth study of the roles of lncRNA in nasopharyngeal carcinoma (NPC) carcinogenesis might be helpful to provide novel therapeutic targets. Here we report that lncRNA TINCR was significantly upregulated in NPC and was associated positively with poor survival. Silencing TINCR inhibited NPC progression and cisplatin resistance. Mechanistically, TINCR bound ACLY and protected it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. Accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulated the peptidyl arginine deiminase 1 (PADI1)-MAPK-MMP2/9 pathway. In addition, insulin-like growth factor 2 mRNA-binding protein 3 interacted with TINCR and slowed its decay, which partially accounted for TINCR upregulation in NPC. These findings demonstrate that TINCR acts as a crucial driver of NPC progression and chemoresistance and highlights the newly identified TINCR-ACLY-PADI1-MAPK-MMP2/9 axis as a potential therapeutic target in NPC. SIGNIFICANCE: TINCR-mediated regulation of a PADI1-MAPK-MMP2/9 signaling pathway plays a critical role in NPC progression and chemoresistance, marking TINCR as a viable therapeutic target in this disease.