Dual topologies of proteins at the ER membrane are known for a variety of proteins allowing the same protein to exert different functions according to the topology adopted. A dual topology of the co-chaperone ERdj4, which resides in the endoplasmic reticulum (ER), was proposed recently, a thesis that we found to align all published data and existing controversies into one whole picture. The aim of this review is to reassess all primary data available in the literature on ER-resident Hsp40 co-chaperones with respect to their topology. After careful and critical analyses of all experimental data published so far, we identified, next to ERdj4, two other co-chaperones, ERdj3 and ERdj6, that also display features of a dual topology at the ER membrane. We assume that during cellular stress subpools of some ER-resident J protein can alter their topology so that these proteins can exert different functions in order to adapt to cellular stress.
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, IRE1α, 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.
The endoplasmic reticulum (ER) of mammalian cells is the central organelle for the maturation and folding of transmembrane proteins and for proteins destined to be secreted into the extracellular space. The proper folding of target proteins is achieved and supervised by a complex endogenous chaperone machinery. BiP, a member of the Hsp70 protein family, is the central chaperone in the ER. The chaperoning activity of BiP is assisted by ER-resident DnaJ (ERdj) proteins due to their ability to stimulate the low, intrinsic ATPase activity of BiP. Besides their co-chaperoning activity, ERdj proteins also regulate and tightly control the translation, translocation, and degradation of proteins. Disturbances in the luminal homeostasis result in the accumulation of unfolded proteins, thereby eliciting a stress response, the so-called unfolded protein response (UPR). Accumulated proteins are either deleterious due to the functional loss of the respective protein and/or due to their deposition as intra- or extracellular protein aggregates. A variety of metabolic diseases are known to date, which are associated with the dysfunction of components of the chaperone machinery. In this review, we will delineate the impact of ERdj proteins in controlling protein synthesis and translocation under physiological and under stress conditions. A second aspect of this review is dedicated to the role of ERdj proteins in the ER-associated degradation pathway, by which unfolded or misfolded proteins are discharged from the ER. We will refer to some of the most prominent diseases known to be based on the dysfunction of ERdj proteins.
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