Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression

Abstract

The unfolded protein response (UPR) maintains protein homeostasis by governing the processing capacity of the endoplasmic reticulum (ER) to manage ER client loads; however, key regulators within the UPR remain to be identified. Activation of the UPR sensor PERK (EIFAK3/PEK) results in the phosphorylation of the ␣ subunit of eIF2 (eIF2␣-P), which represses translation initiation and reduces influx of newly synthesized proteins into the overloaded ER. As part of this adaptive response, eIF2␣-P also induces a feedback mechanism through enhanced transcriptional and translational expression of Gadd34 (Ppp1r15A), which targets type 1 protein phosphatase for dephosphorylation of eIF2␣-P to restore protein synthesis. Here we describe a novel mechanism by which Gadd34 expression is regulated through the activity of the zinc finger transcription factor NMP4 (ZNF384, CIZ). NMP4 functions to suppress bone anabolism, and we suggest that this occurs due to decreased protein synthesis of factors involved in bone formation through NMP4-mediated dampening of Gadd34 and c-Myc expression. Loss of Nmp4 resulted in an increase in c-Myc and Gadd34 expression that facilitated enhanced ribosome biogenesis and global protein synthesis. Importantly, protein synthesis was sustained during pharmacological induction of the UPR through a mechanism suggested to involve GADD34-mediated dephosphorylation of eIF2␣-P. Sustained protein synthesis sensitized cells to pharmacological induction of the UPR, and the observed decrease in cell viability was restored upon inhibition of GADD34 activity. We conclude that NMP4 is a key regulator of ribosome biogenesis and the UPR, which together play a central role in determining cell viability during endoplasmic reticulum stress.Professional secretory cells balance the synthesis, folding, and trafficking of proteins to ensure optimal protein export.Upon differentiation and physiological cues, increased synthesis of polypeptides slated for secretion can lead to accumulation of unfolded proteins in the endoplasmic reticulum (ER) 3 that trigger the unfolded protein response (UPR) (1). The UPR features multiple sensory proteins, including PERK (EIF2AK3/ PEK), IRE1 (ERN1), and ATF6, which are each situated in the ER and are activated by unfolded proteins in the ER (1). Induction of the UPR leads to a program of translational and transcriptional gene expression that collectively serve to expand the processing capacity of the ER to effectively manage an expanded ER client load (1).In response to ER stress, PERK phosphorylates the ␣ subunit of eIF2 (eIF2␣-P), which represses global translation initiation that reduces influx of newly synthesized proteins into the overloaded ER (2, 3). Coincident with dampening of global protein synthesis, eIF2␣-P leads to preferential translation of Atf4, encoding a transcription activator of UPR genes involved in nutrient import, metabolism, and alleviation of oxidative stress (4 -6). ATF4 also directly induces the transcriptional expression of Gadd34 (Ppp1r15A), which targets ty...

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