title: The conserved npl4 protein complex mediates proteasome-dependent membrane-bound transcription factor activation.
abstract: Proteolytic activation of membrane-bound transcription factors has emerged as an important mechanism for the regulation of gene expression. Two membrane-bound transcription factors regulated in this manner are the Saccharomyces cerevisiae proteins Mga2p and Spt23p, which direct transcription of the Delta9-fatty acid desaturase gene OLE1. We now show that a membrane-associated complex containing the highly conserved Npl4p, Ufd1p, and Cdc48p proteins mediates the proteasome-regulated cleavage of Mga2p and Spt23p. Mutations in NPL4, UFD1, and CDC48 cause a block in Mga2p and Spt23p processing, with concomitant loss of OLE1 expression. Taken together, our data indicate that the Npl4 complex may serve to target the proteasome to the ubiquitinated endoplasmic reticulum membrane-bound proteins Mga2p and Spt23p. Given the recent finding that NPL4 is allelic to the ERAD gene HRD4, we further propose that this NPL4 function extends to all endoplasmic reticulum-membrane-associated targets of the proteasome.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Hitchcock
authors.forename: H
authors.initials: H
authors.lastname: Krebber
authors.forename: S
authors.initials: S
authors.lastname: Frietze
authors.forename: A
authors.initials: A
authors.lastname: Lin
authors.forename: M
authors.initials: M
authors.lastname: Latterich
authors.forename: P A
authors.initials: PA
authors.lastname: Silver
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans; D018797:Cell Cycle Proteins / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics* / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D004330:Drosophila; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D044943:Fatty Acid Desaturases / Q000235:genetics; D005656:Fungal Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D006801:Humans; D007425:Intracellular Membranes; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009685:Nuclear Envelope / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013230:Stearoyl-CoA Desaturase; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000074405:Valosin Containing Protein; D015003:Yeasts
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; C104361:NPL4 protein, S cerevisiae; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D011506:Proteins; C119430:RPN4 protein, S cerevisiae; C087570:SPT23 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C491497:UFD1 protein, human; D044943:Fatty Acid Desaturases; D013230:Stearoyl-CoA Desaturase; C029627:delta-9 fatty acid desaturase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614177:CDC48 protein, S cerevisiae; D000074405:Valosin Containing Protein