The Nuclear Inclusion a (NIa) Protease of Turnip Mosaic Virus (TuMV) Cleaves Amyloid-beta

Abstract

Background: The nuclear inclusion a (NIa) protease of turnip mosaic virus (TuMV) is responsible for the processing of the viral polyprotein into functional proteins. NIa was previously shown to possess a relatively strict substrate specificity with a preference for Val-Xaa-His-Gln down arrow, with the scissile bond located after Gln. The presence of the same consensus sequence, Val(12)-His-His-Gln(15), near the presumptive alpha-secretase cleavage site of the amyloid-beta (A beta) peptide led us to hypothesize that NIa could possess activity against A beta. Methodology/Principal Findings: Western blotting results showed that oligomeric as well as monomeric forms of A beta can be degraded by NIa in vitro. The specific cleavage of A beta was further confirmed by mass spectrometry analysis. NIa was shown to exist predominantly in the cytoplasm as observed by immunofluorescence microscopy. The overexpression of NIa in B103 neuroblastoma cells resulted in a significant reduction in cell death caused by both intracellularly generated and exogenously added A beta. Moreover, lentiviral-mediated expression of NIa in APP(sw)/PS1 transgenic mice significantly reduced the levels of A beta and plaques in the brain. Conclusions/Significance: These results indicate that the degradation of A beta in the cytoplasm could be a novel strategy to control the levels of A beta, plaque formation, and the associated cell death.