And Yet It Moves: Oxidation of the Nuclear Autoantigen La/SS-B Is the Driving Force for Nucleo-Cytoplasmic Shuttling

• Published in: International journal of molecular sciences Vol. 22; no. 18; p. 9699
• Main Authors: Berndt, Nicole, Bippes, Claudia C, Michalk, Irene, Bartsch, Tabea, Arndt, Claudia, Puentes-Cala, Edinson, Soto, Javier Andrés, Loureiro, Liliana R, Kegler, Alexandra, Bachmann, Dominik, Gross, Joanne K, Gross, Tim, Kurien, Biji T, Scofield, R Hal, Farris, A Darise, James, Judith A, Bergmann, Ralf, Schmitz, Marc, Feldmann, Anja, Bachmann, Michael P
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.09.2021; MDPI
• Subjects: Active Transport, Cell Nucleus; anti-La/SS-B antibodies; Antibodies; Antibodies, Monoclonal - chemistry; Antigens; Autoantigens - chemistry; autoimmunity; Cell culture; Cell Nucleus - metabolism; Cytoplasm; Cytoplasm - metabolism; Dendritic cells; Deprivation; Endothelial cells; Epitopes - chemistry; Green Fluorescent Proteins - metabolism; HEK293 Cells; Humans; Hydrogen peroxide; La protein; La/SS-B autoantigen; Ligands; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; Monoclonal antibodies; Nitric Oxide - metabolism; Oxidation; Oxidation-Reduction; Oxidative stress; Oxygen - chemistry; primary Sjögren’s Syndrome; Protein Conformation; Protein transport; Proteins; redox sensor; Reducing agents; Ribonucleoproteins - chemistry; RNA polymerase; Signal Transduction; Sjogren's Syndrome - immunology; Sjogren's Syndrome - metabolism; SS-B Antigen; systemic lupus erythematosus; Toll-like receptors; Ultraviolet radiation; Ultraviolet Rays; shuttling of La protein; systemic lupus erythematosus; autoimmunity; primary Sjögren’s Syndrome; redox sensor; anti-La/SS-B antibodies; La/SS-B autoantigen
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22189699

Decades ago, we and many other groups showed a nucleo-cytoplasmic translocation of La protein in cultured cells. This shuttling of La protein was seen after UV irradiation, virus infections, hydrogen peroxide exposure and the Fenton reaction based on iron or copper ions. All of these conditions are somehow related to oxidative stress. Unfortunately, these harsh conditions could also cause an artificial release of La protein. Even until today, the shuttling and the cytoplasmic function of La/SS-B is controversially discussed. Moreover, the driving mechanism for the shuttling of La protein remains unclear. Recently, we showed that La protein undergoes redox-dependent conformational changes. Moreover, we developed anti-La monoclonal antibodies (anti-La mAbs), which are specific for either the reduced form of La protein or the oxidized form. Using these tools, here we show that redox-dependent conformational changes are the driving force for the shuttling of La protein. Moreover, we show that translocation of La protein to the cytoplasm can be triggered in a ligand/receptor-dependent manner under physiological conditions. We show that ligands of toll-like receptors lead to a redox-dependent shuttling of La protein. The shuttling of La protein depends on the redox status of the respective cell type. Endothelial cells are usually resistant to the shuttling of La protein, while dendritic cells are highly sensitive. However, the deprivation of intracellular reducing agents in endothelial cells makes endothelial cells sensitive to a redox-dependent shuttling of La protein.