Dimerization of visinin-like protein 1 is regulated by oxidative stress and calcium and is a pathological hallmark of amyotrophic lateral sclerosis

AbstractRedox control of proteins that form disulfide bonds upon oxidative challenge is an emerging topic in the physiological and pathophysiological regulation of protein function. We have investigated the role of the neuronal calcium sensor protein visinin-like protein 1 (VILIP-1) as a novel redox sensor in a cellular system. We have found oxidative stress to trigger dimerization of VILIP-1 within a cellular environment and identified thioredoxin reductase as responsible for facilitating the remonomerization of the dimeric protein. Dimerization is modulated by calcium and not dependent on the myristoylation of VILIP-1. Furthermore, we show by site-directed mutagenesis that dimerization is exclusively mediated by Cys187. As a functional consequence, VILIP-1 dimerization modulates the sensitivity of cells to an oxidative challenge. We have investigated whether dimerization of VILIP-1 occurs in two different animal models of amyotrophic lateral sclerosis (ALS) and detected soluble VILIP-1 dimers to be significantly enriched in the spinal cord from phenotypic disease onset onwards. Moreover, VILIP-1 is part of the ALS-specific protein aggregates. We show for the first time that the C-terminus of VILIP-1, containing Cys187, might represent a novel redox-sensitive motif and that VILIP-1 dimerization and aggregation are hallmarks of ALS. This suggests that VILIP-1 dimers play a functional role in integrating the cytosolic calcium concentration and the oxidative status of the cell. Furthermore, a loss of VILIP-1 function owing to protein aggregation in ALS could be relevant in the pathophysiology of the disease

It's all about talking: two-way communication between proteasomal and lysosomal degradation pathways via ubiquitin

Selective degradation of proteins requires a fine-tuned coordination of the two major proteolytic pathways, the ubiquitin-proteasome system (UPS) and autophagy. Substrate selection and proteolytic activity are defined by a plethora of regulatory cofactors influencing each other. Both proteolytic pathways are initiated by ubiquitylation to mark substrate proteins for degradation, although the size and/or topology of the modification are different. In this context E3 ubiquitin ligases, ensuring the covalent attachment of activated ubiquitin to the substrate, are of special importance. The regulation of E3 ligase activity, competition between different E3 ligases for binding E2 conjugation enzymes and substrates, as well as their interplay with deubiquitylating enzymes (DUBs) represent key events in the cross talk between the UPS and autophagy. The coordination between both degradation routes is further influenced by heat shock factors and ubiquitin-binding proteins (UBPs) such as p97, p62, or optineurin. Mutations in enzymes and ubiquitin-binding proteins or a general decline of both proteolytic systems during aging result in accumulation of damaged and aggregated proteins. Thus further mechanistic understanding of how UPS and autophagy communicate might allow therapeutic intervention especially against age-related diseases