FIGURE 5.

Model for NMP4 regulation of ribosome biogenesis and the UPR. NMP4 serves to dampen transcriptional expression of c-Myc and Gadd34, which are important for regulation of ribosome biogenesis and eIF2α-P and the UPR, respectively. ER stress and induction of the UPR in Nmp4^+/+ cells results in decreased protein synthesis that promotes stress alleviation, partially through the regulated expression of c-Myc and Gadd34. However, in Nmp4^−/− cells there are high levels of c-Myc and Gadd34 expression and subsequent elevation of ribosome biogenesis and translation initiation through GADD34-mediated dephosphorylation of eIF2α-P. As a consequence, heightened levels of synthesized proteins slated to be retained in the cytosol and those directed into the ER for secretion are maintained during pharmacological induction of the UPR, thwarting stress adaptation that renders cells sensitive to the acute ER stress. Loss of Nmp4 has also been shown to increase bone anabolism in mice, which is likely due, at least in part, to increased c-MYC- and GADD34-mediated protein synthesis and secretion.