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.

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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