An I?B Kinase-Regulated Feedforward Circuit Prolongs Inflammation.

ABSTRACT: Loss of NF-?B signaling causes immunodeficiency, whereas inhibition of NF-?B can be efficacious in treating chronic inflammatory disease. Inflammatory NF-?B signaling must therefore be tightly regulated, and although many mechanisms to downregulate NF-?B have been elucidated, there have only been limited studies demonstrating positive feedforward regulation of NF-?B 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-?B activation. Phosphorylation of ITCH by IKKs leads to impaired ITCH E3 ubiquitin ligase activity and prolongs NF-?B 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-?B activation that drives inflammatory disease.

SUBMITTER: Perez JM 

PROVIDER: S-EPMC4520735 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature