Ubiquitin complexes that limit inflammation and cytokine production in allergy

Children'S Hosp Of Philadelphia, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

DESCRIPTION (provided by applicant): Chronic allergic diseases, such as asthma, affect millions of individuals world wide and can be life threatening. Despite new therapeutic approaches, the incidence of asthma is on the rise and many patients' symptoms are not adequately controlled. These diseases are often driven by allergen-specific T cells. While the role of CD4+ TH2 cells and their production of IL-4, IL-5 and IL-13 has been well-established, what causes these cytokine producing T cells to lose control and drive inflammation in the absence of pathogen invasion is not well understood. Genome wide association studies (GWAS) studies have identified defects in pathways that regulate cytokine production by these TH2 cells. One pathway that regulates TH2 production and lung inflammation in both mouse and man involves the E3 ubiquitin ligase Itch. We have identified an E3 ubiquitin ligase adaptor, Nedd4-family interacting protein 1 (Ndfip1), that activates several E3 ubiquitin ligases, including Itch, to limit TH2 cell differentiation and proinflammatory cytokine production. Our published data suggest that Ndfip1 prevents T cell activation, TH2 differentiation and consequent lung inflammation characterized by goblet cell hyperplasia and eosinophilia. Our preliminary data reveal the mechanistic underpinnings of how Ndfip1 activates E3 ubiquitin ligases like Itch. These results may define a new paradigm for activation of Itch as well as other Nedd4-family members. Based on these studies, we have designed a novel approach for therapeutic activation of these E3 ligases to treat allergic disease. This proposal is centered on testing two interrelated hypotheses. We hypothesize that Ndfip1 relieves autoinhibition of Itch to limit proinflammatory cytokine production in T cells. We hypothesize that therapeutic mimics of Ndfip1 can be used to activate ubiquitylation cascades to limit TH2 cytokine production and to reduce lung inflammation. Experiments described in this proposal will determine the key biochemical features that allow Ndfip1 to trigger Itch activation, and test whether Ndfip1 peptides can be used to limit proinflammatory cytokine production in TH2 cells. Additionally, using quantitative proteomics, we will determine the underlying mechanisms of how Ndfip1 regulates proinflammatory cytokine production in TH2 cells. While this proposal is focused on testing the therapeutic potential using mouse models of T cell-mediated inflammation in the lung, these data could have broad implications for designing therapies to treat allergic diseases such as asthma.