title: Inducible turnover of optineurin regulates T cell activation.
abstract: Optineurin (Optn) is an adaptor protein with homology to NF-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase (IKK) complex. Dysregulation of Optn has been linked to neurodegenerative, autoimmune and bone diseases. Optn shares a high degree of homology with NEMO, but is not part of the same high-molecular weight complex containing IKKα and IKKβ. Despite its homology with NEMO and the fact that it has been the subject of extensive study in several cell types, there are no published studies addressing the role of Optn during T cell activation. Here we demonstrate that ectopic expression of Optn down-regulates TCR-induced NF-κB activation and TNF-α production, in a manner dependent on ubiquitin-binding. Conversely, knock-down of Optn enhances NF-κB activation and the production of TNF-α. Consistent with a negative regulatory role for this protein, we observed transient loss of Optn after TCR stimulation in both cell lines and in primary murine T cells. The acute loss of Optn appears to be due to both protein degradation and exocytosis, the latter via activation-induced exosomes. This study therefore provides novel information regarding the role of Optn during TCR activation, suggesting the possible importance of Optn during inflammation and/or autoimmune diseases.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States.
authors.forename: Angela
authors.initials: A
authors.lastname: Montecalvo
authors.affiliation: Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.affiliation: Texas Children's Hospital, Houston, TX 77030, United States.
authors.forename: Jordan
authors.initials: J
authors.lastname: Orange
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States. Electronic address: lkane@pitt.edu.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Kane
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002460:Cell Line; D005136:Eye Proteins / Q000276:immunology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D035582:Transcription Factor TFIIIA / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D005136:Eye Proteins; D026901:Membrane Transport Proteins; D016328:NF-kappa B; C409460:OPTN protein, human; C501288:Optn protein, mouse; D035582:Transcription Factor TFIIIA; D014409:Tumor Necrosis Factor-alpha
keywords: Extracellular vesicles; NF-kappa B (NF-κB); Optineurin; T cells; T-cell receptor for antigen (TCR)