Reticulon1-C modulates protein disulphide isomerase function

• Published in: Cell death & disease Vol. 4; no. 4; p. e581
• Main Authors: Bernardoni, P, Fazi, B, Costanzi, A, Nardacci, R, Montagna, C, Filomeni, G, Ciriolo, M R, Piacentini, M, Di Sano, F
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2013; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/45/470/1981; 631/67/1922; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line, Tumor; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Endoplasmic Reticulum Stress - genetics; Gene Expression Regulation; Humans; Immunology; Life Sciences; Microtubules - metabolism; Microtubules - ultrastructure; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Original; original-article; Protein Disulfide-Isomerases - genetics; Protein Disulfide-Isomerases - metabolism; Protein Folding; Protein Isoforms - genetics; Protein Isoforms - metabolism; Signal Transduction; Transport Vesicles - metabolism; Transport Vesicles - ultrastructure; reticulon; protein disulfide isomerase; endoplamic reticulum
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2013.113

Endoplasmic reticulum (ER) is the primary site for the synthesis and folding of secreted and membrane-bound proteins. Accumulation of unfolded and misfolded proteins in ER underlies a wide range of human neurodegenerative disorders. Hence, molecules regulating the ER stress response represent potential candidates as drug targets for tackling these diseases. Protein disulphide isomerase (PDI) is a chaperone involved in ER stress pathway, its activity being an important cellular defense against protein misfolding. Here, we demonstrate that human neuroblastoma SH-SY5Y cells overexpressing the reticulon protein 1-C (RTN1-C) reticulon family member show a PDI punctuate subcellular distribution identified as ER vesicles. This represents an event associated with a significant increase of PDI enzymatic activity. We provide evidence that the modulation of PDI localization and activity does not only rely upon ER stress induction or upregulation of its synthesis, but tightly correlates to an alteration in its nitrosylation status . By using different RTN1-C mutants, we demonstrate that the observed effects depend on RTN1-C N-terminal region and on the integrity of the microtubule network. Overall, our results indicate that RTN1-C induces PDI redistribution in ER vesicles, and concomitantly modulates its activity by decreasing the levels of its S -nitrosylated form. Thus RTN1-C represents a promising candidate to modulate PDI function.