Arsenite-Activated JNK Signaling Enhances CPEB4-Vinexin Interaction to Facilitate Stress Granule Assembly and Cell Survival

Yu-Wei Chang,Yi-Shuian Huang,Eric Jan

doi:10.1371/journal.pone.0107961

Abstract

Stress granules (SGs) are compartmentalized messenger ribonucleoprotein particles (mRNPs) where translationally repressed mRNAs are stored when cells encounter environmental stress. Cytoplasmic polyadenylation element-binding protein (CPEB)4 is a sequence-specific RNA-binding protein and translational regulator. In keeping with the results obtained from the study of other RNA-binding proteins, we found CPEB4 localized in SGs in various arsenite-treated cells. In this study, we identified that Vinexin, a CPEB4-interacting protein, is a novel component of SGs. Vinexin is a SH3-domain-containing adaptor protein and affects cell migration through its association with Vinculin to localize at focal adhesions (FAs). Unexpectedly, Vinexin is translocated from FAs to SGs under arsenite-induced stress. The recruitment of Vinexin to SGs depends on its interaction with CPEB4 and influences SG formation and cell survival. Arsenite-activated c-Jun N-terminal kinase (JNK) signaling enhances the association between CPEB4 and Vinexin, which consequently facilitates SG localization of Vinexin. Taken together, this study uncovers a novel interaction between a translational regulator and an adaptor protein to influence SG assembly and cell survival.

Highlights

Cytoplasmic mRNAs are dynamically associated with a variety of RNA-binding proteins to control their subcellular localization, stability and translation
Because CPEB1 has been found at the leading edge of migrating astrocytes where it regulates local translation of b-catenin RNA [35] and all Cytoplasmic polyadenylation element-binding protein (CPEB) are nucleocytoplasm-shuttling proteins with longer retention time in the cytoplasm [19,20,21,22,36], we surmised that the interaction with Vinexin could change subcellular distribution of CPEB4
Myc-CPEB4 was not recruited to focal adhesions (FAs) or nucleus by Vinexin a or b; instead, both Vinexin isoforms were localized at Stress granules (SGs) in CPEB4-overexressing cells (Figure 1D)

Summary

Introduction

Cytoplasmic mRNAs are dynamically associated with a variety of RNA-binding proteins to control their subcellular localization, stability and translation. These processes are often interconnected and occur in compartmentalized RNA foci. The stalled initiation complex including 40S ribosomal subunits, eIF2a and many other eIFs, as well as mRNAs and RNA-binding proteins, aggregate and accumulate in SGs [1,2]. Several RNA-binding proteins involved in neurodegeneration, such as Fused in sarcoma (FUS), TAR DNA-binding protein of 43 kDa (TDP-43) and Ataxin 2, are the components of SGs. several RNA-binding proteins involved in neurodegeneration, such as Fused in sarcoma (FUS), TAR DNA-binding protein of 43 kDa (TDP-43) and Ataxin 2, are the components of SGs Accumulation of these proteins in SGs was controversially reported to promote or slow down irreversible aggregation of these proteins [7,8,9]

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