The function of the co-chaperone ERdj4 in diverse (patho-)physiological conditions

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces a well-orchestrated cellular response to reduce the protein burden within the ER. This unfolded protein response (UPR) is controlled primarily by three transmembrane proteins, IRE1 alpha, ATF6, and PERK, the activity of which is controlled by BiP, the ER-resident Hsp70 protein. Binding of BiP to co-chaperones via their highly conserved J-domains stimulates the intrinsic ATPase activity of BiP, thereby providing the energy necessary for (re-)folding of proteins, or for targeting of misfolded proteins to the degradation pathway, processes specified and controlled by the respective co-chaperone. In this review, our aim is to elucidate the function of the co-chaperone ERDJ4, also known as MDG1, MDJ7, or DNAJB9. Knockout and knockin experiments clearly point to the central role of ERDJ4 in controlling lipogenesis and protein synthesis by promoting degradation of SREBP1c and the assembly of the protein complex mTORC2. Accumulating data reveal that ERDJ4 controls epithelial-to-mesenchymal transition, a central process during embryogenesis, in wound healing, and tumor development. Overexpression of ERdj4 has been shown to improve engraftment of transplanted human stem cells, possibly due to its ability to promote cellular survival in stressed cells. High ERDJ4-plasma levels are specific for fibrillary glomerulonephritis and serve as a diagnostic marker. As outlined in this review, the functions of ERDJ4 are manifold, depending on the cellular (patho-) physiological state, the cellular protein repertoire, and the subcellular localization of ERDJ4.

Automated summary

The accumulation of misfolded proteins in the endoplasmic reticulum triggers a cellular response known as the unfolded protein response (UPR), which is primarily controlled by three transmembrane proteins IRE1 alpha, ATF6, and PERK, with the activity regulated by the ER-resident Hsp70 protein BiP. The co-chaperone ERDJ4 plays a central role in controlling lipogenesis and protein synthesis by promoting the degradation of SREBP1c and the assembly of the protein complex mTORC2, as well as regulating epithelial-to-mesenchymal transition and cellular survival in stressed cells.