| First Author | Perez JM | Year | 2015 |
| Journal | Cell Rep | Volume | 12 |
| Issue | 4 | Pages | 537-44 |
| PubMed ID | 26190110 | Mgi Jnum | J:277039 |
| Mgi Id | MGI:6274041 | Doi | 10.1016/j.celrep.2015.06.050 |
| Citation | Perez JM, et al. (2015) An IkappaB Kinase-Regulated Feedforward Circuit Prolongs Inflammation. Cell Rep 12(4):537-44 |
| abstractText | Loss of NF-kappaB signaling causes immunodeficiency, whereas inhibition of NF-kappaB can be efficacious in treating chronic inflammatory disease. Inflammatory NF-kappaB signaling must therefore be tightly regulated, and although many mechanisms to downregulate NF-kappaB have been elucidated, there have only been limited studies demonstrating positive feedforward regulation of NF-kappaB 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-kappaB activation. Phosphorylation of ITCH by IKKs leads to impaired ITCH E3 ubiquitin ligase activity and prolongs NF-kappaB 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-kappaB activation that drives inflammatory disease. |
