The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation
| Autor: | Nicole I. Orazio, Jenny P.-Y. Ting, Thomas J. Kelly, Jae U. Jung, Mary A. Rodgers, Qiming Liang, Hiroaki Fujita, Mude Shi, Rina Amatya, Kazuhiro Iwai, James W. Bowman |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Lipopolysaccharides
Inflammasomes Ubiquitin-Protein Ligases Immunology Interleukin-1beta Regulator Inflammation Biology Article AIM2 Mice Immune system Ubiquitin NLR Family Pyrin Domain-Containing 3 Protein medicine Immunology and Allergy Animals Humans Secretion Mice Knockout Innate immune system integumentary system Macrophages GTPase-Activating Proteins Intracellular Signaling Peptides and Proteins NF-kappa B Ubiquitination Inflammasome Immunity Innate 3. Good health Cell biology Common Variable Immunodeficiency Multiprotein Complexes biology.protein medicine.symptom Carrier Proteins medicine.drug |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 |
| Popis: | Independent of its known role in NF-κB transcription, the HOIL-1L containing LUBAC is required for assembly and activation of the NLRP3 inflammasome via linear ubiquitination of ASC. Linear ubiquitination is a newly discovered posttranslational modification that is currently restricted to a small number of known protein substrates. The linear ubiquitination assembly complex (LUBAC), consisting of HOIL-1L, HOIP, and Sharpin, has been reported to activate NF-κB–mediated transcription in response to receptor signaling by ligating linear ubiquitin chains to Nemo and Rip1. Despite recent advances, the detailed roles of LUBAC in immune cells remain elusive. We demonstrate a novel HOIL-1L function as an essential regulator of the activation of the NLRP3/ASC inflammasome in primary bone marrow–derived macrophages (BMDMs) independently of NF-κB activation. Mechanistically, HOIL-1L is required for assembly of the NLRP3/ASC inflammasome and the linear ubiquitination of ASC, which we identify as a novel LUBAC substrate. Consequently, we find that HOIL-1L−/− mice have reduced IL-1β secretion in response to in vivo NLRP3 stimulation and survive lethal challenge with LPS. Together, these data demonstrate that linear ubiquitination is required for NLRP3 inflammasome activation, defining the molecular events of NLRP3 inflammasome activation and expanding the role of LUBAC as an innate immune regulator. Furthermore, our observation is clinically relevant because patients lacking HOIL-1L expression suffer from pyogenic bacterial immunodeficiency, providing a potential new therapeutic target for enhancing inflammation in immunodeficient patients. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|