Studies of nuclear receptor corepressor, NRIP1, in vitamin A signaling pathways

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DESCRIPTION (provided by applicant): Retinoic acid (RA), the biologically active form of vitamin A, acts, primarily, by binding to nuclear RA receptor (RAR) and retinoid receptor X (RXR) to regulate gene expression. But the activities of RAR and RXR ultimately depend on the recruitment of coregulators. The project has initially focused on an RA-dependent RAR corepressor named Nuclear Receptor Interacting Protein 1 (NRIP1, also known as RIP140), which was later found as a wide spectrum coregulator for many other transcription factors. Previous progress includes systemic characterization of NRIP1 with regards to its wide spectrum corepressive activity in RA-targeted genes, functional domains, and post-translational modifications (PTMs) that alter its property and subcellular localization (i.e., export into cytoplasm) to elicit additional biological activities beyond RA gene regulation. These novel non-genomic activities of NRIP1 were demonstrated in regulating insulin sensitivity, glucose uptake, lipolysis and adiponectin secretion in adipocytes. The genomic and non-genomic activities of NRIP1 together establish its critical role in the development and progression of metabolic diseases in relation to vitamin A signaling. More recent results revealed a new role for NRIP1 in controlling innate immunity by enhancing M1 and repressing M2 macrophages. This is modulated by RA and also affects RA synthesis capacity in macrophages. We hypothesize that i) NRIP1 acts as a specific coregulator in a cell-context and chromatin-locus dependent manner, i.e., it can be a coactivator or a corepressor depending upon the type of transcription factor it interacts, the cellular state and specific chromatin loci, ii) NRIP1's versatility is reglated by PTM and is relevant to RA homeostasis, and iii) NRIP1's versatility enhances macrophage genome plasticity (or epigenetics) in response to nutritional (vitamin A) or pathological challenges. We propose two aims to address these hypotheses. Aim 1 will address the molecular mechanisms of NRIP1's differential coregulatory functions in macrophages. Aim 2 will determine the physiological and nutritional relevance of NRIP1 in innate immunity control by exploiting a macrophage-specific NRIP1-knockdown mouse model with or without vitamin A deficiency. This mouse model shows reduced inflammation (M1), improved wound healing (M2) and elevated RA synthesizing enzyme RALDH2 mRNA level. We will also employ rescue strategies by using various NRIP1 proteins mutated in specific PTMs. The results will be key to future translational application of targeting NRIP1, such as in maintaining the homeostasis of nutritional (vitamin A) and metabolic status, and in managing metabolic diseases.