N4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization

Hexin Shi, Lei Sun, Ying Wang, Aijie Liu, Xiaoming Zhan, Xiaohong Li, Miao Tang, Priscilla Anderton, Sara Hildebrand, Jiexia Quan, Sara Ludwig, Eva Marie Y. Moresco and Bruce Beutler ()
Additional contact information
Hexin Shi: University of Texas Southwestern Medical Center
Lei Sun: University of Texas Southwestern Medical Center
Ying Wang: University of Texas Southwestern Medical Center
Aijie Liu: University of Texas Southwestern Medical Center
Xiaoming Zhan: University of Texas Southwestern Medical Center
Xiaohong Li: University of Texas Southwestern Medical Center
Miao Tang: University of Texas Southwestern Medical Center
Priscilla Anderton: University of Texas Southwestern Medical Center
Sara Hildebrand: University of Texas Southwestern Medical Center
Jiexia Quan: University of Texas Southwestern Medical Center
Sara Ludwig: University of Texas Southwestern Medical Center
Eva Marie Y. Moresco: University of Texas Southwestern Medical Center
Bruce Beutler: University of Texas Southwestern Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Many immune responses depend upon activation of NF-κB, an important transcription factor in the elicitation of a cytokine response. Here we show that N4BP1 inhibits TLR-dependent activation of NF-κB by interacting with the NF-κB signaling essential modulator (NEMO, also known as IκB kinase γ) to attenuate NEMO–NEMO dimerization or oligomerization. The UBA-like (ubiquitin associated-like) and CUE-like (ubiquitin conjugation to ER degradation-like) domains in N4BP1 mediate interaction with the NEMO COZI domain. Both in vitro and in mice, N4bp1 deficiency specifically enhances TRIF-independent (TLR2, TLR7, or TLR9-mediated) but not TRIF-dependent (TLR3 or TLR4-mediated) NF-κB activation, leading to increased production of proinflammatory cytokines. In response to TLR4 or TLR3 activation, TRIF causes activation of caspase-8, which cleaves N4BP1 distal to residues D424 and D490 and abolishes its inhibitory effect. N4bp1−/− mice also have diminished numbers of T cells in the peripheral blood. Our work identifies N4BP1 as an inhibitory checkpoint protein that must be overcome to activate NF-κB, and a TRIF-initiated caspase-8-dependent mechanism by which this is accomplished.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-21711-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21711-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-21711-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().