| First Author | Gitlin AD | Year | 2020 |
| Journal | Nature | Volume | 587 |
| Issue | 7833 | Pages | 275-280 |
| PubMed ID | 32971525 | Mgi Jnum | J:297419 |
| Mgi Id | MGI:6472603 | Doi | 10.1038/s41586-020-2796-5 |
| Citation | Gitlin AD, et al. (2020) Integration of innate immune signalling by caspase-8 cleavage of N4BP1. Nature 587(7833):275-280 |
| abstractText | Mutations in the death receptor FAS(1,2) or its ligand FASL(3) cause autoimmune lymphoproliferative syndrome, whereas mutations in caspase-8 or its adaptor FADD-which mediate cell death downstream of FAS and FASL-cause severe immunodeficiency in addition to autoimmune lymphoproliferative syndrome(4-6). Mouse models have corroborated a role for FADD-caspase-8 in promoting inflammatory responses(7-12), but the mechanisms that underlie immunodeficiency remain undefined. Here we identify NEDD4-binding protein 1 (N4BP1) as a suppressor of cytokine production that is cleaved and inactivated by caspase-8. N4BP1 deletion in mice increased the production of select cytokines upon stimulation of the Toll-like receptor (TLR)1-TLR2 heterodimer (referred to herein as TLR1/2), TLR7 or TLR9, but not upon engagement of TLR3 or TLR4. N4BP1 did not suppress TLR3 or TLR4 responses in wild-type macrophages, owing to TRIF- and caspase-8-dependent cleavage of N4BP1. Notably, the impaired production of cytokines in response to TLR3 and TLR4 stimulation of caspase-8-deficient macrophages(13) was largely rescued by co-deletion of N4BP1. Thus, the persistence of intact N4BP1 in caspase-8-deficient macrophages impairs their ability to mount robust cytokine responses. Tumour necrosis factor (TNF), like TLR3 or TLR4 agonists, also induced caspase-8-dependent cleavage of N4BP1, thereby licensing TRIF-independent TLRs to produce higher levels of inflammatory cytokines. Collectively, our results identify N4BP1 as a potent suppressor of cytokine responses; reveal N4BP1 cleavage by caspase-8 as a point of signal integration during inflammation; and offer an explanation for immunodeficiency caused by mutations of FADD and caspase-8. |
