Splicing modulators elicit global translational repression by condensate-prone proteins translated from introns.
Cell Chem Biol
; 29(2): 259-275.e10, 2022 02 17.
Article
em En
| MEDLINE
| ID: mdl-34520743
ABSTRACT
Chemical splicing modulators that bind to the spliceosome have provided an attractive avenue for cancer treatment. Splicing modulators induce accumulation and subsequent translation of a subset of intron-retained mRNAs. However, the biological effect of proteins containing translated intron sequences remains unclear. Here, we identify a number of truncated proteins generated upon treatment with the splicing modulator spliceostatin A (SSA) via genome-wide ribosome profiling and bio-orthogonal noncanonical amino acid tagging (BONCAT) mass spectrometry. A subset of these truncated proteins has intrinsically disordered regions, forms insoluble cellular condensates, and triggers the proteotoxic stress response through c-Jun N-terminal kinase (JNK) phosphorylation, thereby inhibiting the mTORC1 pathway. In turn, this reduces global translation. These findings indicate that creating an overburden of condensate-prone proteins derived from introns represses translation and prevents further production of harmful truncated proteins. This mechanism appears to contribute to the antiproliferative and proapoptotic activity of splicing modulators.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Splicing de RNA
/
Spliceossomos
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Proteínas Quinases JNK Ativadas por Mitógeno
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Alvo Mecanístico do Complexo 1 de Rapamicina
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Cell Chem Biol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Japão