ArticleScience immunology2017
Citrullination of NF-κB p65 promotes its nuclear localization and TLR-induced expression of IL-1β and TNFα.
Article in Science immunology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
72 citing papers in PubMed, 1 synthesis or guideline pooled it, 116 citations in OpenAlex.
- Role of the PADI family in inflammatory autoimmune diseases and cancers: A systematic review.Frontiers in immunology · 2023Pooled it
- PAD4 deletion in synovial macrophages exacerbates pathology in inflammatory arthritis.Research square · 2026Article
- Beyond PAD Inhibition: Emerging Avenues and Natural Products for Targeting Citrullination in Immune Diseases.Biomedicines · 2026Review
- Regulation of basal and tumour necrosis factor α-induced fibroblast gene expression by peptidylarginine deiminase 2.The Journal of physiology · 2026Article
- Natural Products Targeting PAD4 in NETosis: Structural and Mechanistic Insights into Direct and Indirect Inhibition.Biomolecules · 2026Review
- Role of LIGHT in the Inflammatory Mechanisms of Psoriasis via Upregulation of Proliferation and Cytokine Production of Keratinocytes.Immunity, inflammation and disease · 2026Article
- Peptidylarginine deiminase 4-mediated citrullination in human disease: molecular mechanisms and therapeutic targeting.Frontiers in pharmacology · 2026Review
- Peptidylarginine deiminase 2 contributes to pathogenesis in trinitrobenzenesulfonic acid-induced colitis through macrophage extracellular trap-independent pathways.Scientific reports · 2025Article
- Citrullination in tumor immunity and therapy.The Journal of clinical investigation · 2025Review
- Citrullination in health and disease: From physiological function to gene regulation.Genes & diseases · 2025Review
- Citrullination of NF-κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute Lung Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Protocatechuic Acid Attenuates Inflammation in Macrophage-like Vascular Smooth Muscle Cells in ApoENutrients · 2025Article
- Astragaloside IV- loaded biomimetic nanoparticles target IκBα to regulate neutrophil extracellular trap formation for sepsis therapy.Journal of nanobiotechnology · 2025Article
- Citrullinated IGF2BP1 promotes rheumatoid synovial aggression via increasing the mRNA stability of SEMA3D.Communications biology · 2025Article
- Peptidylarginine deiminase 4 deficiency alleviates hypoxia/reoxygenation-induced cardiomyocyte injury.PloS one · 2025Article
- Redundant role of PAD2 and PAD4 in the development of cardiovascular lesions in a mouse model of Kawasaki disease vasculitis.Clinical and experimental immunology · 2024Article
- A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV regulation.Nature communications · 2024Article
- The role of anti-citrullinated protein antibody in pathogenesis of RA.Clinical and experimental medicine · 2024Review
- Reciprocal regulation of protein arginine deiminase 2 and 4 expression in the colonic mucosa of ulcerative colitis.Journal of clinical biochemistry and nutrition · 2024Article
- Neutrophil-derived PAD4 induces citrullination of CKMT1 exacerbates mucosal inflammation in inflammatory bowel disease.Cellular & molecular immunology · 2024Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
Abstract
Many citrullinated proteins are known autoantigens in rheumatoid arthritis, a disease mediated by inflammatory cytokines, such as tumor necrosis factor-α (TNFα). Citrullinated proteins are generated by converting peptidylarginine to peptidylcitrulline, a process catalyzed by the peptidylarginine deiminases (PADs), including PAD1 to PAD4 and PAD6. Several major risk factors for rheumatoid arthritis are associated with heightened citrullination. However, the physiological role of citrullination in immune cells is poorly understood. We report that suppression of PAD activity attenuates Toll-like receptor-induced expression of interleukin-1β (IL-1β) and TNFα by neutrophils in vivo and in vitro but not their global transcription activity. Mechanistically, PAD4 directly citrullinates nuclear factor κB (NF-κB) p65 and enhances the interaction of p65 with importin α3, which brings p65 into the nucleus. The citrullination-enhanced interaction of p65 with importin α3 and its nuclear translocation and transcriptional activity can be attributed to citrullination of four arginine residues located in the Rel homology domain of p65. Furthermore, a rheumatoid arthritis-prone variant of PAD4, carrying three missense mutations, is more efficient in interacting with p65 and enhancing NF-κB activity. Together, these data not only demonstrate a critical role of citrullination in an NF-κB-dependent expression of IL-1β and TNFα but also provide a molecular mechanism by which heightened citrullination propagates inflammation in rheumatoid arthritis. Accordingly, attenuating p65-mediated production of IL-1β and TNFα by blocking the citrullination of p65 has great therapeutic potential in rheumatoid arthritis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.