Research ArticleAUTOIMMUNITY

Citrullination of NF-κB p65 promotes its nuclear localization and TLR-induced expression of IL-1β and TNFα

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Science Immunology  09 Jun 2017:
Vol. 2, Issue 12, eaal3062
DOI: 10.1126/sciimmunol.aal3062

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PADs inflame arthritis

Individuals with rheumatoid arthritis (RA) produce an autoimmune response to citrullinated proteins that may contribute to disease pathology. Sun et al. report that citrullination also directly contributes to RA-associated inflammation. They found that decreased activity of peptidylarginine deiminases (PADs), which catalyze peptide citrullination, limited TLR-induced expression of the proinflammatory cytokines IL-1β and TNFα by neutrophils. PAD4 directly citrullinated the proinflammatory signaling molecule NF-κB p65, enhancing transport into the nucleus. An RA-associated human variant of PAD4 interacted more closely with NF-κB p65, thereby augmenting NF-κB activity. These data suggest that the interaction between PADs and NF-κB p65 may serve as a more specific target to treat RA.