signature=577f630fb15e3c59338fffb9bca5a98c,The Role of MK-STYX in the eIF2alpha Stress Response Path...

摘要：

The pseudophosphatase MK-STYX (mitogen activated kinase phosphoserine/threonine/tyrosine binding protein) is a member of the MAPK phosphatases (MKP) dual specificity phosphatase family. However, it has the residues FSX5R, instead of HCX5R in its signature active motif. We previously reported that MK-STYX interacts with the RNA binding protein G3BP1 (Ras-GTPase SH3 domain binding protein-1) in the stress response pathway. During the stress response, mRNA translation is halted. Cytoplasmic compartments known as stress granules form around mRNA and RNA binding proteins, such as G3BP1, until the cell determines their fate. Dephosphorylation of G3BP1 at S149 induces stress granule formation. Previously, we showed that MK-STYX interaction with G3BP1 and inhibition of stress granule formation are not dependent on the phosphorylation status of the G3BP1 at S149, suggesting that MK-STYX inhibits stress granule formation by some other mechanism. The stress granule life cycle (assembly, persistence, and disassembly) may be controlled through translation, which is governed by the eIF2 alpha pathway and downstream through the Hsp 70 pathway. To elucidate the molecular mechanism of MK-STYX in the stress granule life cycle, we investigated its role in these two pathways. Translation is governed by the eukaryotic initiation factor 2 alpha (eIF2α). When eIF2α is phosphorylated, translation is halted and when it is not phosphorylated, polysome formation occurs. Our immunoprecipitation studies revealed that eIF2α and MK-STYX interact. Overexpression of eIF2αlpha in non-heat stressed and heat stressed HeLa cells showed that eIF2α phosphorylation decreased in the presence of MK-STYX. However, overexpression of MK-STYX in arsenite stressed cells showed no change in eIF2α phosphorylation. In addition, knockdown of MK-STYX in heat stressed and arsenite stressed cells showed no difference in eIF2α phosphorylation. Furthermore, MK-STYX showed no effect on the HSP70 family protein Binding Immunoglobuling Protein (BiP) in arsenite stressed cells. However, taken together, these results reveal that there is a specific mechanism for the pseudophosphatase MK-STYX in inhibiting stress granule assembly in non-heat stressed and heat stressed cells.

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