RRC ID 68073
Author Park J, Lee J, Kim JH, Lee J, Park H, Lim C.
Title ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD.
Journal 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.
Volume 49(19)
Pages 11294-11311
Published 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
Drosophila 4887R-3 4901R-3 4901R-4 5013R-2 5013R-3 6013R-2 7069R-1 7069R-2 7470R-2 7470R-3 8064R-1 11027R-2 8064R-2 11027R-3 8635R-2 30170R-1 8635R-3 30170R-2 9323R-2 4155R-1 4155R-2 9323R-4 9379R-2 8711R-1 9379R-3 8711R-2 9429R-1 9429R-2 11181R-1 5366R-3 5366R-4 11181R-3 18811R-1 4886R-1 18811R-2 3193R-2 4886R-4 10289R-2 11454R-3 11183R-2 11454R-4 9054R-2 11563R-1 12736R-2 9054R-3 15014R-1 15014R-2 8863R-2 18596R-2 8863R-3 18596R-3 2691R-1 17596R-1 2691R-2 17596R-2 2931R-2 2931R-3 3016R-1 3016R-2 14730R-3 12168R-1 12168R-2 31643R-1 31643R-2 31961R-3 31961R-4 6316R-1 6316R-2 3436R-2 3436R-3 3608R-1 4622R-2 4849R-1 4849R-3 2677R-2 2677R-3 4153R-2 4153R-8 10161R-2 10161R-3 8335R-1 8335R-7 4878R-3 4035R-1 10847R-2 10847R-3 17654R-1 17654R-2 5605R-1 5605R-2 10372R-1 1945R-1 4535R-3 11171R-1 11171R-2 2094R-2 2094R-3 3949R-1 3949R-3 10377R-1 10377R-7 6603R-1 6603R-3 4183R-1 4183R-3 31449R-2 31449R-6 14207R-1 14207R-3 9484R-1 9484R-2 4924R-2 4924R-3 1972R-1 1972R-2 3298R-1 3298R-2 2922R-1 2922R-2 4152R-1 4152R-2 4533R-1 4533R-2 10578R-1 10578R-2 2684R-1 2684R-3 6311R-2 6311R-3 4916R-1 9738R-1 9738R-3 5479R-1 5479R-2 8274R-2 7421R-3 7421R-4 1884R-3 8426R-3 31716R-1 10868R-1 10868R-5 5993R-1 5993R-2 11486R-3 11486R-4 8201R-1 10695R-1 10695R-2 8241R-3 8241R-4 11940R-2 11940R-3 2055R-1 2055R-2 10371R-1 10371R-2 12306R-2 12306R-3 13383R-2 13383R-3 12217R-1 12217R-2 4212R-2 4212R-3 7111R-1 7111R-2 10057R-1 9635R-2 9635R-3 11171R-1 11171R-2 7305R-1 7305R-2 5422R-1 31237R-2 31318R-1 3180R-3 5271R-3 5271R-7 8922R-1 16944R-1 16944R-2 32423R-2 32423R-3 5263R-3 5263R-2 5263R-3 8954R-4 6369R-3 8571R-2 8571R-3 16725R-2 16725R-3 1536R-3 1536R-4 18497R-1 18497R-4 32451R-2 32451R-4 13472R-1 13472R-3 5092R-1 5092R-2 10686R-3 10686R-4 2253R-1 2253R-3 11184R-2 4170R-1 4170R-3 1973R-3 12076R-1 12076R-2 5215R-2 5215R-3