Cytoplasmic Translocation, Aggregation, and Cleavage of TDP43 by Enteroviral Proteases Modulate Viral Pathogenesis and Enhance Viral Infectivity

TitleCytoplasmic Translocation, Aggregation, and Cleavage of TDP43 by Enteroviral Proteases Modulate Viral Pathogenesis and Enhance Viral Infectivity
Publication TypeJournal Article
Year of Publication2015
AuthorsFung, G, Shi, J, Deng, H, Hou, J, Wang, C, Hong, A, Zhang, J, Jia, W, Luo, H
JournalCell Death and Differentiation
Volume22
Issue12
Pagination2087-2097
Date Published12/2015
ISSNPrint: 1350-9047; Online: 1476-5403
Abstract

We have previously demonstrated that infection by coxsackievirus B3 (CVB3), a positive-stranded RNA enterovirus, results in the accumulation of insoluble ubiquitin–protein aggregates, which resembles the common feature of neurodegenerative diseases. The importance of protein aggregation in viral pathogenesis has been recognized; however, the underlying regulatory mechanisms remain ill-defined. Transactive response DNA-binding protein-43 (TDP-43) is an RNA-binding protein that has an essential role in regulating RNA metabolism at multiple levels. Cleavage and cytoplasmic aggregation of TDP-43 serves as a major molecular marker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration and contributes significantly to disease progression. In this study, we reported that TDP-43 is translocated from the nucleus to the cytoplasm during CVB3 infection through the activity of viral protease 2A, followed by the cleavage mediated by viral protease 3C. Cytoplasmic translocation of TDP-43 is accompanied by reduced solubility and increased formation of protein aggregates. The cleavage takes place at amino-acid 327 between glutamine and alanine, resulting in the generation of an N- and C-terminal cleavage fragment of ~35 and ~8 kDa, respectively. The C-terminal product of TDP-43 is unstable and quickly degraded through the proteasome degradation pathway, whereas the N-terminal truncation of TDP-43 acts as a dominant-negative mutant that inhibits the function of native TDP-43 in alternative RNA splicing. Lastly, we demonstrated that knockdown of TDP-43 results in an increase in viral titers, suggesting a protective role for TDP-43 in CVB3 infection. Taken together, our findings suggest a novel model by which cytoplasmic redistribution and cleavage of TDP-43 as a consequence of CVB3 infection disrupts the solubility and transcriptional activity of TDP-43. Our results also reveal a mechanism evolved by enteroviruses to support efficient viral infection.

DOI10.1038/cdd.2015.58