Abstract
According to the literature, the autoantigen La is involved in Cap-independent translation. It was proposed that one prerequisite for this function is the formation of a protein dimer. However, structural analyses argue against La protein dimers. Noteworthy to mention, these structural analyses were performed under reducing conditions. Here we describe that La protein can undergo redox-dependent structural changes. The oxidized form of La protein can form dimers, oligomers and even polymers stabilized by disulfide bridges. The primary sequence of La protein contains three cysteine residues. Only after mutation of all three cysteine residues to alanine La protein becomes insensitive to oxidation, indicating that all three cysteines are involved in redox-dependent structural changes. Biophysical analyses of the secondary structure of La protein support the redox-dependent conformational changes. Moreover, we identified monoclonal anti-La antibodies (anti-La mAbs) that react with either the reduced or oxidized form of La protein. Differential reactivities to the reduced and oxidized form of La protein were also found in anti-La sera of autoimmune patients.
Highlights
Almost five decades ago, autoantibodies to the autoantigens La and Ro, known as Sjögren’s syndrome associated antigen B (SS-B) and SS-A, were first detected in sera of patients suffering from primary Sjögren’s syndrome or systemic lupus erythematosus (SLE) [1,2]
We show that La protein undergoes redox-dependent conformational changes
The original cloning and reclonings were screened by ELISA using recombinantly expressed human La protein
Summary
Autoantibodies to the autoantigens La and Ro, known as Sjögren’s syndrome associated antigen B (SS-B) and SS-A, were first detected in sera of patients suffering from primary Sjögren’s syndrome (pSS) or systemic lupus erythematosus (SLE) [1,2]. As part of the diagnosis, sera of patients are commonly analyzed for the presence of anti-nuclear antibodies (ANAs) using immunofluorescence (IF) microscopy According to these countless microscopical analyses, there is certainly no doubt about a nuclear localization of La protein [3]. Nuclear localization is in good agreement with the described nuclear function(s) of La protein in the context of primary RNA polymerase III transcripts [4,5,6,7,8,9] Besides these nuclear functions, it was published that La protein may play an additional role in the cytoplasmic compartment: It was shown that La protein is involved in Cap-independent translation of viral and cellular mRNAs harboring internal ribosomal entry sites (IRES elements) [8,9,10,11,12,13]. A nuclear retention element (NRE) and a nucleolar localization signal (NoLS) were identified inside of the same region [15,16] (Figure 1A, and below)
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