Abstract
Stress granules (SG) are membrane-less organelles that are condensates of stalled translation initiation complexes and mRNAs. SG formation is a cytoprotective response to environmental stress and results from protein interactions involving regions of low amino acid complexity and poorly defined post-translational modifications of SG components. Many RNA-binding proteins are methylated, and we previously demonstrated that the potent SG-nucleating protein G3BP1 is methylated by protein arginine methyltransferase 1 and 5 (PRMT1 and PRMT5). G3BP1 methylation represses SG formation and is reversible. Here we functionally link JMJD6 (Jumonji C domain-containing protein 6) to G3BP1 demethylation. Our findings reveal that JMJD6 is a novel SG component that interacts with G3BP1 complexes, and its expression reduces G3BP1 monomethylation and asymmetric dimethylation at three Arg residues. Knockdown of JMJD6 repressed SG formation and G3BP1 demethylation, but SG formation and G3BP1 demethylation were rescued with catalytically active but not mutant JMJD6. These results suggest that JMJD6 functions directly or indirectly as an arginine demethylase of G3BP1 that promotes SG formation.
Highlights
Stress granules (SG) are membrane-less organelles that are condensates of stalled translation initiation complexes and mRNAs
Immunofluorescence analysis (IFA) indicated that JMJD6 was most strongly localized in the nucleus (Fig. 1a, top panels), which agreed with previous studies from other groups [48, 49]
To test whether G3BP1 interacts with JMJD6, we immunoprecipitated G3BP1 from unstressed and arsenite-stressed cells followed by Western blotting to detect JMJD6 in G3BP1 complexes
Summary
MRNA to prevent mRNA degradation [7], as platforms for innate immune activation of double-stranded RNA-dependent protein kinase PKR [8, 9], and function as mediators of signaling cascades (10 –13). SG formation typically follows translation inhibition caused by stress-induced eIF2␣ phosphorylation [1, 2, 14, 15], disruption of eIF4A and eIF4G function with small molecule inhibitors or virus infection [16] [17], and stress-induced tRNA cleavage (18 –21) via an eIF2␣-independent pathway Some of these RNA-binding proteins have been characterized as SG–nucleating proteins, G3BP1 and Tia. Rescue experiments showed that expression of wild-type JMJD6, but not a catalytically inactive mutant, caused demethylation of G3BP1 and promoted SG assembly during arsenite stress. These data indicate that catalytic activity of JMJD6 results in G3BP1 demethylation that triggers SG assembly during oxidative stress and strongly suggest methylated G3BP1 is a substrate of JMJD6
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