Other
13 Authors
- Wang Y,
- Hildebrand S,
- Moresco EMY,
- Shi H,
- Beutler B,
- Tang M,
- Ludwig S,
- Zhan X,
- Liu A,
- Quan J,
- Anderton P,
- Sun L,
- Li X
| First Author | Shi H | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 1379 |
| PubMed ID | 33654074 | Mgi Jnum | J:304890 |
| Mgi Id | MGI:6515137 | Doi | 10.1038/s41467-021-21711-5 |
| Citation | Shi H, et al. (2021) N4BP1 negatively regulates NF-kappaB by binding and inhibiting NEMO oligomerization. Nat Commun 12(1):1379 |
| abstractText | Many immune responses depend upon activation of NF-kappaB, an important transcription factor in the elicitation of a cytokine response. Here we show that N4BP1 inhibits TLR-dependent activation of NF-kappaB by interacting with the NF-kappaB signaling essential modulator (NEMO, also known as IkappaB kinase gamma) 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-kappaB 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-kappaB, and a TRIF-initiated caspase-8-dependent mechanism by which this is accomplished. |
