Citrullination of NF-kappaB p65 promotes its nuclear localization and TLR-induced expression of IL-1beta and TNFalpha
Authors
Sun, BoDwivedi, Nishant
Bechtel, Tyler J.
Paulsen, Janet L.
Muth, Aaron
Bawadekar, Mandar
Li, Gang
Thompson, Paul R
Shelef, Miriam A.
Schiffer, Celia A.
Weerapana, Eranthie
Ho, I-Cheng
UMass Chan Affiliations
Schiffer LabThompson Lab
Department of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2017-06-09
Metadata
Show full item recordAbstract
Many citrullinated proteins are known autoantigens in rheumatoid arthritis, a disease mediated by inflammatory cytokines, such as tumor necrosis factor-alpha (TNFalpha). 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-1beta (IL-1beta) and TNFalpha by neutrophils in vivo and in vitro but not their global transcription activity. Mechanistically, PAD4 directly citrullinates nuclear factor kappaB (NF-kappaB) p65 and enhances the interaction of p65 with importin alpha3, which brings p65 into the nucleus. The citrullination-enhanced interaction of p65 with importin alpha3 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-kappaB activity. Together, these data not only demonstrate a critical role of citrullination in an NF-kappaB-dependent expression of IL-1beta and TNFalpha but also provide a molecular mechanism by which heightened citrullination propagates inflammation in rheumatoid arthritis. Accordingly, attenuating p65-mediated production of IL-1beta and TNFalpha by blocking the citrullination of p65 has great therapeutic potential in rheumatoid arthritis.Source
Sci Immunol. 2017 Jun 9;2(12). pii: eaal3062. doi: 10.1126/sciimmunol.aal3062. Link to article on publisher's site
DOI
10.1126/sciimmunol.aal3062Permanent Link to this Item
http://hdl.handle.net/20.500.14038/48875PubMed ID
28783661Related Resources
ae974a485f413a2113503eed53cd6c53
10.1126/sciimmunol.aal3062