Targeting the Zinc Transporter ZIP7 in the Treatment of Insulin Resistance and Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is a disease associated with dysfunctional metabolic processes that lead to abnormally high levels of blood glucose. Preceding the development of T2DM is insulin resistance (IR), a disorder associated with suppressed or delayed responses to insulin. The effects of this response are predominately mediated through aberrant cell signalling processes and compromised glucose uptake into peripheral tissue including adipose, liver and skeletal muscle. Moreover, a major factor considered to be the cause of IR is endoplasmic reticulum (ER) stress. This subcellular organelle plays a pivotal role in protein folding and processes that increase ER stress, leads to maladaptive responses that result in cell death. Recently, zinc and the proteins that transport this metal ion have been implicated in the ER stress response. Specifically, the ER-specific zinc transporter ZIP7, coined the "gate-keeper" of zinc release from the ER into the cytosol, was shown to be essential for maintaining ER homeostasis in intestinal epithelium and myeloid leukaemia cells. Moreover, ZIP7 controls essential cell signalling pathways similar to insulin and activates glucose uptake in skeletal muscle. Accordingly, ZIP7 may be essential for the control of ER localized zinc and mechanisms that disrupt this process may lead to ER-stress and contribute to IR. Accordingly, understanding the mechanisms of ZIP7 action in the context of IR may provide opportunities to develop novel therapeutic options to target this transporter in the treatment of IR and subsequent T2DM

Biochemical investigation of zinc transporters to discover their functional mechanism in cells

Zinc is one of the most abundant micronutrients in the human body and it plays a vital role in many normal cellular processes. The cellular zinc level is tightly controlled by zinc transporters, including the ZIP family, which function to increase cytosolic zinc levels. The alteration of this function has been associated with human diseases, including cancer. ZIP7 belongs to the ZIP family of zinc transporters and resides on the endoplasmic reticulum store. It is responsible for releasing zinc from stores after it has been phosphorylated by CK2 on residues S275 and S276. This ZIP7-mediated zinc release inhibits tyrosine phosphatases and activates cellular tyrosine kinases, several of which are associated with progression of cancer. Moreover, two other ZIP transporters, namely ZIP6 and ZIP10, have been demonstrated to be involved in cell growth and proliferation by importing zinc across biological membranes to cause cell rounding and detachment, essential for migration and the first step of mitosis. In order to achieve this, the N-terminus of ZIP6 has to be cleaved before these transporters relocate to the plasma membrane. The present study generated novel constructs to understand the functional mechanisms of these transporters. Firstly, the activation of ZIP7 was investigated by mutating all four residues S275, S276, S293 and T294 predicted to be phosphorylated. This study found that all four of these residues were required for ZIP7 maximal activation. Secondly, the role of N-terminal cleavage of ZIP6 and ZIP10 was investigated by making chimera constructs replacing the usually cleaved N-terminus with the ZIP7 N-terminus, known not to be cleaved. This study found that the N-terminal cleavage of ZIP6 and ZIP10 was required to enable the cells to round up and detach, indicating a critical role for the N-terminus of ZIP6 and ZIP10 in this mechanism. These findings not only help us to understand the mechanism for these transporters but also enable new tools to be discovered for diseases, such as cancer, that are exacerbated by these transporters