title: Degradation of Stop Codon Read-through Mutant Proteins via the Ubiquitin-Proteasome System Causes Hereditary Disorders.
abstract: During translation, stop codon read-through occasionally happens when the stop codon is misread, skipped, or mutated, resulting in the production of aberrant proteins with C-terminal extension. These extended proteins are potentially deleterious, but their regulation is poorly understood. Here we show in vitro and in vivo evidence that mouse cFLIP-L with a 46-amino acid extension encoded by a read-through mutant gene is rapidly degraded by the ubiquitin-proteasome system, causing hepatocyte apoptosis during embryogenesis. The extended peptide interacts with an E3 ubiquitin ligase, TRIM21, to induce ubiquitylation of the mutant protein. In humans, 20 read-through mutations are related to hereditary disorders, and extended peptides found in human PNPO and HSD3B2 similarly destabilize these proteins, involving TRIM21 for PNPO degradation. Our findings indicate that degradation of aberrant proteins with C-terminal extension encoded by read-through mutant genes is a mechanism for loss of function resulting in hereditary disorders.
authors.affiliation: Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Shibata
authors.affiliation: Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Ohoka
authors.affiliation: Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba 277-8561, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sugaki
authors.affiliation: Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba 277-8561, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Onodera
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sakuraba
authors.affiliation: Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takakura
authors.affiliation: Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Hashii
authors.affiliation: Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Nana
authors.initials: N
authors.lastname: Kawasaki
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.affiliation: Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan. Electronic address: miki-naito@nihs.go.jp.
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Naito
mesh_terms: D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics* / Q000378:metabolism; D018388:Codon, Terminator; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006720:Homozygote; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D012261:Ribonucleoproteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D000099207:SS-A Antigen
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018388:Codon, Terminator; D046988:Proteasome Endopeptidase Complex; D012261:Ribonucleoproteins; D025801:Ubiquitin; D000099207:SS-A Antigen; C506387:Cflar protein, mouse
keywords: HSD3B2; PNPO; TRIM21; apoptosis; cFLIP-L; mutagenesis; proteasome; read-through mutation; ubiquitin; ubiquitylation (ubiquitination)