title: Mif1: a missing link between the unfolded protein response pathway and ER-associated protein degradation?
abstract: Eukaryotic cells have three different mechanisms to deal with the accumulation of unfolded proteins in the endoplasmic reticulum: (1) In cells in which unfolded polypeptides accumulate, translation initiation is inhibited to prevent further accumulation of unfolded proteins. (2) Expression of proteins involved in polypeptide folding is strongly enhanced by a process called the Unfolded Protein Response (UPR). (3) Proteins missing the proper tertiary structure are degraded by the ER-Associated protein Degradation (ERAD) mechanism. Recent studies in S. cerevisiae have shown that the processes of UPR and ERAD are functionally linked to each other. Cells lacking a functional ERAD show a constitutive activation of UPR. In addition, many of the components of ERAD are under the direct transcriptional control of UPR. Finally, while neither UPR nor ERAD are essential for cell viability, deletion of both pathways results in severe growth impairment. UPR and ERAD are conserved between yeast and mammalian cells. One of the components of mammalian UPR is the protease presenilin-1. Mutations in the gene for presenilin-1 cause early-onset familial Alzheimer disease. Interestingly, inhibition of proteolysis by the ubiquitin-26S proteasome system has also been described for Alzheimer s disease. This suggests a link between UPR and ERAD in mammalian cells. The recently identified gene Mif1 is a possible candidate to form a direct link between UPR and ERAD in mammalian cells. The Mif1 gene is under the direct control of UPR. Mif1 is a trans-ER-membrane protein, with both the N- and the C-termini facing the cytoplasmic side of the ER membrane. It contains an N-terminal ubiquitin-like domain. It is anticipated that Mif1 may associate through its ubiquitin-like domain with the 26S proteasome, in this way connecting the protein degradation machinery to the ER membrane and resulting in an efficient ERAD.
authors.affiliation: MGC-Department of Radiation Genetics and Chemical Mutagenesis, P. O. Box 9503, 2300 RA Leiden, the Netherlands. T.van_Laar@LUMC.nl
authors.forename: T
authors.initials: T
authors.lastname: van Laar
authors.forename: A J
authors.initials: AJ
authors.lastname: van der Eb
authors.forename: C
authors.initials: C
authors.lastname: Terleth
mesh_terms: D051702:Activating Transcription Factor 6; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010447:Peptide Hydrolases / Q000378:metabolism; D053764:Presenilin-1; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D004722:Endoribonucleases; D008565:Membrane Proteins; D010447:Peptide Hydrolases; D053764:Presenilin-1; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C485932:HERPUD1 protein, human; C508853:PSEN1 protein, human; C403982:ERN2 protein, human; C486556:Ern2 protein, mouse; C061553:ATP dependent 26S protease