N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammation Journal Article
| Authors: | Gitlin, A. D.; Maltzman, A.; Kanno, Y.; Heger, K.; Reja, R.; Schubert, A. F.; Wierciszewski, L. J.; Pantua, H.; Kapadia, S. B.; Harris, S. F.; Webster, J. D.; Newton, K.; Dixit, V. M. |
| Article Title: | N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammation |
| Abstract: | The ubiquitin-binding endoribonuclease N4BP1 potently suppresses cytokine production by Toll-like receptors (TLRs) that signal through the adaptor MyD88 but is inactivated via caspase-8-mediated cleavage downstream of death receptors, TLR3, or TLR4. Here, we examined the mechanism whereby N4BP1 limits inflammatory responses. In macrophages, deletion of N4BP1 prolonged activation of inflammatory gene transcription at late time points after TRIF-independent TLR activation. Optimal suppression of inflammatory cytokines by N4BP1 depended on its ability to bind polyubiquitin chains, as macrophages and mice-bearing inactivating mutations in a ubiquitin-binding motif in N4BP1 displayed increased TLR-induced cytokine production. Deletion of the noncanonical IκB kinases (ncIKKs), Tbk1 and Ikke, or their adaptor Tank phenocopied N4bp1 deficiency and enhanced macrophage responses to TLR1/2, TLR7, or TLR9 stimulation. Mechanistically, N4BP1 acted in concert with the ncIKKs to limit the duration of canonical IκB kinase (IKKα/β) signaling. Thus, N4BP1 and the ncIKKs serve as an important checkpoint against over-exuberant innate immune responses. © 2024 Elsevier Inc. |
| Keywords: | signal transduction; controlled study; unclassified drug; human cell; gene deletion; genetics; nonhuman; ubiquitin; protein function; animal cell; mouse; animal; metabolism; animals; mice; mice, knockout; embryo; animal experiment; inflammation; genetic transcription; in vivo study; enzyme activity; protein serine threonine kinase; mice, inbred c57bl; c57bl mouse; cytokine; immunology; cytokines; adaptor proteins, signal transducing; i kappa b kinase beta; cytokine production; innate immunity; molecular interaction; macrophage; macrophages; phosphotransferase; signal transducing adaptor protein; polyubiquitin; toll like receptor; toll like receptor 2; knockout mouse; i kappa b kinase; toll-like receptors; endoribonucleases; ribonuclease; toll like receptor 9; toll like receptor 1; i-kappa b kinase; toll like receptor 7; i kappa b kinase epsilon; cytokine response; human; female; article; tlr signaling; tank binding kinase 1; protein serine-threonine kinases; i kappa b kinase alpha; n4bp1 protein |
| Journal Title: | Immunity |
| Volume: | 57 |
| Issue: | 5 |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press |
| Date Published: | 2024-05-14 |
| Start Page: | 973 |
| End Page: | 986.e7 |
| Language: | English |
| DOI: | 10.1016/j.immuni.2024.04.004 |
| PUBMED: | 38697117 |
| PROVIDER: | scopus |
| PMCID: | PMC11096006 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Alexander Gitlin -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work