title: 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 α subunit of eIF2 (eIF2α-P), which represses translation initiation and reduces influx of newly synthesized proteins into the overloaded ER. As part of this adaptive response, eIF2α-P also induces a feedback mechanism through enhanced transcriptional and translational expression of Gadd34 (Ppp1r15A),which targets type 1 protein phosphatase for dephosphorylation of eIF2α-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 eIF2α-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.
authors.affiliation: From the Department of Biochemistry and Molecular Biology.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Young
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202-5126.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Anatomy and Cell Biology, and jbidwell@iu.edu.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Bidwell
authors.affiliation: From the Department of Biochemistry and Molecular Biology, rwek@iu.edu.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
mesh_terms: D000818:Animals; D015977:Eukaryotic Initiation Factor-1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000096:biosynthesis* / Q000235:genetics; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D015977:Eukaryotic Initiation Factor-1; D034521:Nuclear Matrix-Associated Proteins; D014157:Transcription Factors; C499081:Zfp384 protein, mouse; C026022:eukaryotic peptide initiation factor-1A; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1
keywords: endoplasmic reticulum stress (ER stress); eukaryotic initiation factor 2 (eIF2); protein homeostasis; protein synthesis; translation control; unfolded protein response (UPR)