{"doi":"10.1016/j.jbc.2022.102638","title":"Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling","abstract":"Inflammation contributes to the progression of retinal pathology caused by diabetes. Here, we investigated a role for the stress response protein regulated in development and DNA damage response 1 (REDD1) in the development of retinal inflammation. Increased REDD1 expression was observed in the retina of mice after 16-weeks of streptozotocin (STZ)induced diabetes, and REDD1 was essential for diabetesinduced pro-inflammatory cytokine expression. In human retinal MIO-M1 Mller cell cultures, REDD1 deletion prevented increased pro-inflammatory cytokine expression in response to hyperglycemic conditions. REDD1 deletion promoted nuclear factor erythroid-2-related factor 2 (Nrf2) hyperactivation; however, Nrf2 was not required for reduced inflammatory cytokine expression in REDD1-deficient cells. Rather, REDD1 enhanced inflammatory cytokine expression by promoting activation of nuclear transcription factor B (NF-B). In WT cells exposed to tumor necrosis factor (TNF), inflammatory cytokine expression was increased in coordination with activating transcription factor 4 (ATF4)-dependent REDD1 expression and sustained activation of NF-B. In both Mller cell cultures exposed to TNF and in the retina of STZdiabetic mice, REDD1 deletion promoted inhibitor of B (IB) expression and reduced NF-B DNA-binding activity. We found that REDD1 acted upstream of IB by enhancing both K63-ubiquitination and auto-phosphorylation of IB kinase complex. In contrast with STZ-diabetic REDD1 +/+ mice, IB kinase complex autophosphorylation and macrophage infiltration were not observed in the retina of STZ-diabetic REDD1 -/-mice. The findings provide new insight into how diabetes promotes retinal inflammation and support a model wherein REDD1 sustains activation of canonical NF-B signaling.","journal":"Journal of Biological Chemistry","year":2022,"id":256917,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":453863,"name":"Allyson L. Toro","orcid":null,"position":1,"is_corresponding":false},{"id":906283,"name":"Christopher M. McCurry","orcid":"0000-0003-0657-2547","position":2,"is_corresponding":false},{"id":513604,"name":"Ashley M. VanCleave","orcid":"0000-0002-2033-1822","position":3,"is_corresponding":false},{"id":452863,"name":"Shaunaci A. Stevens","orcid":"0000-0001-6904-1618","position":4,"is_corresponding":false},{"id":906284,"name":"William P. Miller","orcid":"0000-0003-0157-6389","position":5,"is_corresponding":false},{"id":369105,"name":"Scot R. Kimball","orcid":"0000-0002-2149-7189","position":6,"is_corresponding":false},{"id":452865,"name":"Michael D. Dennis","orcid":"0000-0002-0645-6864","position":7,"is_corresponding":false},{"id":452862,"name":"Siddharth Sunilkumar","orcid":"0000-0003-3271-932X","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T00:25:25.728895Z","pmid":"36309088","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}