Integration of innate immune signalling by caspase-8 cleavage of N4BP1

Alexander D. Gitlin (), Klaus Heger, Alexander F. Schubert, Rohit Reja, Donghong Yan, Victoria C. Pham, Eric Suto, Juan Zhang, Youngsu C. Kwon, Emily C. Freund, Jing Kang, Anna Pham, Roger Caothien, Natasha Bacarro, Trent Hinkle, Min Xu, Brent S. McKenzie, Benjamin Haley, Wyne P. Lee, Jennie R. Lill, Merone Roose-Girma, Monika Dohse, Joshua D. Webster, Kim Newton () and Vishva M. Dixit ()
Additional contact information
Alexander D. Gitlin: Stanford University School of Medicine
Klaus Heger: Genentech
Alexander F. Schubert: Genentech
Rohit Reja: Genentech
Donghong Yan: Genentech
Victoria C. Pham: Proteomics and Lipidomics, Genentech
Eric Suto: Genentech
Juan Zhang: Genentech
Youngsu C. Kwon: Genentech
Emily C. Freund: Genentech
Jing Kang: Genentech
Anna Pham: Genentech
Roger Caothien: Genentech
Natasha Bacarro: Genentech
Trent Hinkle: Proteomics and Lipidomics, Genentech
Min Xu: Genentech
Brent S. McKenzie: Genentech
Benjamin Haley: Genentech
Wyne P. Lee: Genentech
Jennie R. Lill: Proteomics and Lipidomics, Genentech
Merone Roose-Girma: Genentech
Monika Dohse: Genentech
Joshua D. Webster: Genentech
Kim Newton: Genentech
Vishva M. Dixit: Genentech

Nature, 2020, vol. 587, issue 7833, 275-280

Abstract: Abstract Mutations in the death receptor FAS1,2 or its ligand FASL3 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 syndrome4–6. Mouse models have corroborated a role for FADD–caspase-8 in promoting inflammatory responses7–12, 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 macrophages13 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.

Date: 2020
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DOI: 10.1038/s41586-020-2796-5

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