Unexpected Plasma Membrane Location for a Disulfide Isomerase Protein

The plasma membrane is a fundamental cell compartment necessary to separate the cell interior from the external environment. The membrane regulates the exchange of ions and solutes, is involved in the cell-cell communication and adhesion, as well as in signaling mechanisms. Most of these processes require the participation of specialized proteins, which may be embedded in the phospholipid bilayer or recruited to the cell membrane in response to a particular stimulus. ERp57, a member of the disulfide isomerase family (PDIs), is a soluble protein that is mainly located in the lumen of the endoplasmic reticulum (ER), but that has also been found in the nucleus, cytosol, mitochondria and cell membrane. In the ER, it accomplishes the disulfide bonds reshuffling in newly synthesized glycoproteins, in complex with the lectins calreticulin and calnexin. At present, the functions in the other compartments are still unclear. Several studies have suggested a possible involvement of ERp57 in receptors signalling. On the plasma membrane it has been previously described as being associated with vasopressin and angiotensin II receptors, as well as with STAT3. Furthermore, ERp57 is considered a cell membrane receptor itself in intestinal epithelial cells, where it binds the biologically active form of vitamin D3 (calcitriol) and appears to be responsible for the rapid response to the steroid hormone. In order to investigate these processes, we first analyzed the presence of ERp57 on the plasma membrane in four different cell lines (cancer and immortalized cells) by means of a surface biotinylation method. Our results indicate that ERp57 is present on the plasma membrane of the three analyzed cancer cell lines (HeLa, Raji, M14), but absent in the immortalized one (HaCaT). Moreover, immunofluorescence assays and Western blotting analyses performed in our lab revealed that ERp57 is redistributed in the cell following treatment with calcitriol. Further studies to establish the role of ERp57 in signal transduction and in the protein trafficking from the membrane to the nucleus are presently ongoing.