RRC ID 68073
著者 Park J, Lee J, Kim JH, Lee J, Park H, Lim C.
タイトル ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD.
ジャーナル Nucleic Acids Res
Abstract C9ORF72-derived dipeptide repeat proteins have emerged as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms underlying their expression are not fully understood. Here, we demonstrate that ZNF598, the rate-limiting factor for ribosome-associated quality control (RQC), co-translationally titrates the expression of C9ORF72-derived poly(GR) protein. A Drosophila genetic screen identified key RQC factors as potent modifiers of poly(GR)-induced neurodegeneration. ZNF598 overexpression in human neuroblastoma cells inhibited the nuclear accumulation of poly(GR) protein and decreased its cytotoxicity, whereas ZNF598 deletion had opposing effects. Poly(GR)-encoding sequences in the reporter RNAs caused translational stalling and generated ribosome-associated translation products, sharing molecular signatures with canonical RQC substrates. Furthermore, ZNF598 and listerin 1, the RQC E3 ubiquitin-protein ligase, promoted poly(GR) degradation via the ubiquitin-proteasome pathway. An ALS-relevant ZNF598R69C mutant displayed loss-of-function effects on poly(GR) expression, as well as on general RQC. Moreover, RQC function was impaired in C9-ALS patient-derived neurons, whereas lentiviral overexpression of ZNF598 lowered their poly(GR) expression and suppressed proapoptotic caspase-3 activation. Taken together, we propose that an adaptive nature of the RQC-relevant ZNF598 activity allows the co-translational surveillance to cope with the atypical expression of pathogenic poly(GR) protein, thereby acquiring a neuroprotective function in C9-ALS/FTD.
巻・号 49(19)
ページ 11294-11311
公開日 2021-11-8
DOI 10.1093/nar/gkab834
PII 6374173
PMID 34551427
PMC PMC8565315
MeSH Amyotrophic Lateral Sclerosis / genetics* Amyotrophic Lateral Sclerosis / metabolism Amyotrophic Lateral Sclerosis / pathology Animals C9orf72 Protein / deficiency C9orf72 Protein / genetics* Carrier Proteins / genetics* Carrier Proteins / metabolism Caspase 3 / genetics Caspase 3 / metabolism Cell Line, Tumor Dipeptides / genetics Dipeptides / metabolism Disease Models, Animal Drosophila Proteins / deficiency Drosophila Proteins / genetics Drosophila melanogaster / genetics* Drosophila melanogaster / metabolism Female Frontotemporal Dementia / genetics* Frontotemporal Dementia / metabolism Frontotemporal Dementia / pathology Gene Expression Regulation Gene Knockout Techniques Humans Male Neurons / metabolism Neurons / pathology Proteasome Endopeptidase Complex / metabolism Protein Biosynthesis* Proteolysis Signal Transduction Ubiquitin-Protein Ligases / deficiency Ubiquitin-Protein Ligases / genetics*
IF 11.502
リソース情報
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