Inducible turnover of optineurin regulates T cell activation

• Published in: Molecular immunology Vol. 85; pp. 9 - 17
• Main Authors: Montecalvo, Angela, Watkins, Simon C., Orange, Jordan, Kane, Lawrence P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2017
• Subjects: Animals; autoimmune diseases; Blotting, Western; bone diseases; Cell Line; exocytosis; exosomes; Extracellular vesicles; Eye Proteins - immunology; Eye Proteins - metabolism; Fluorescent Antibody Technique; Gene Knockdown Techniques; Humans; inflammation; Jurkat Cells; Lymphocyte Activation - immunology; Male; Mice; Mice, Inbred C57BL; NF-kappa B (NF-κB); NF-kappa B - immunology; NF-kappa B - metabolism; Optineurin; protein degradation; Real-Time Polymerase Chain Reaction; T cells; T-cell receptor for antigen (TCR); T-lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; transcription factor NF-kappa B; Transcription Factor TFIIIA - immunology; Transcription Factor TFIIIA - metabolism; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; Extracellular vesicles; Optineurin; T cells; T-cell receptor for antigen (TCR); NF-kappa B (NF-κB)
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2017.01.027

•Optineurin (Optn) is expressed in murine and human T cells.•Ectopic expression of Optn suppresses TCR-mediated induction of NF-κB and production of TNF-α.•Knock-down of Optn enhances NF-κB induction and TNF-α production in T cells.•T cell activation leads to rapid loss of endogenous Optn protein, through both degradation and exocytosis in microvesicles. 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.