4.8 Article

ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD

期刊

NUCLEIC ACIDS RESEARCH
卷 49, 期 19, 页码 11294-11311

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OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab834

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资金

  1. Suh Kyungbae Foundation [SUHF-17020101]
  2. National Research Foundation, Republic of Korea [NRF-2018R1A2B2004641, NRF-2018R1A5A1024261, NRF2021R1A2C3011706, NRF-2021M3A9G8022960]
  3. National Research Foundation of Korea [2021M3A9G8022960] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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ZNF598 plays a critical role in regulating the expression of C9ORF72-derived poly(GR) protein through ribosome-associated quality control (RQC) and promotes its degradation via the ubiquitin-proteasome pathway. Moreover, lentiviral overexpression of ZNF598 can reduce the expression of poly(GR) in C9-ALS patient-derived neurons and suppress proapoptotic caspase-3 activation.
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 ZNF598(R69C) 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.

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