| Autor: |
Jessica M. Perez, Steven M. Chirieleison, Derek W. Abbott |
| Jazyk: |
angličtina |
| Rok vydání: |
2015 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 12, Iss 4, Pp 537-544 (2015) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2015.06.050 |
| Popis: |
Loss of NF-κB signaling causes immunodeficiency, whereas inhibition of NF-κB can be efficacious in treating chronic inflammatory disease. Inflammatory NF-κB signaling must therefore be tightly regulated, and although many mechanisms to downregulate NF-κB have been elucidated, there have only been limited studies demonstrating positive feedforward regulation of NF-κB signaling. In this work, we use a bioinformatic and proteomic approach to discover that the IKK family of proteins can phosphorylate the E3 ubiquitin ligase ITCH, a critical downregulator of TNF-mediated NF-κB activation. Phosphorylation of ITCH by IKKs leads to impaired ITCH E3 ubiquitin ligase activity and prolongs NF-κB signaling and pro-inflammatory cytokine release. Since genetic loss of ITCH mirrors IKK-induced ITCH phosphorylation, we further show that the ITCH−/− mouse’s spontaneous lung inflammation and subsequent death can be delayed when TNF signaling is genetically deleted. This work identifies a new positive feedforward regulation of NF-κB activation that drives inflammatory disease. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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