4.5 Article

Splicing modulators elicit global translational repression by condensate-prone proteins translated from introns

期刊

CELL CHEMICAL BIOLOGY
卷 29, 期 2, 页码 259-+

出版社

CELL PRESS
DOI: 10.1016/j.chembiol.2021.07.015

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资金

  1. Japan Society for the Promotion of Science (JSPS) [JP19H05640]
  2. Ministry of Education, Culture, Sports, Science and Technology (MEXT) [JP18H05503]
  3. MEXT [JP17H05679, JP20H05784]
  4. JSPS [JP17H04998, JP19K22406, 20K15420]
  5. Japan Agency for Medical Research and Development (AMED) [JP21gm1410001]
  6. Pioneering Projects (Biology of Intracellular Environments)
  7. Aging Project from RIKEN
  8. Takeda Science Foundation [JP20K15420]
  9. Vincent J. Coates Genomics Sequencing Laboratory at UC Berkeley - NIH [S10 OD018174]
  10. Manabu Ishii, Itoshi Nikaido
  11. Bioinfor-matics Analysis Environment Service on RIKEN Cloud
  12. supercomputer HOKUSAI Sailing Ship in RIKEN ACCC
  13. Japanese Government (MEXT) Scholarship
  14. Grants-in-Aid for Scientific Research [20K15420] Funding Source: KAKEN

向作者/读者索取更多资源

Splicing modulators induce the translation of intron-retained mRNAs, generating truncated proteins. These truncated proteins have intrinsically disordered regions, form insoluble cellular condensates, and trigger the proteotoxic stress response, thereby inhibiting protein synthesis in cells.
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.

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