| RRC ID |
68041
|
| Author |
Chhipi-Shrestha JK, Schneider-Poetsch T, Suzuki T, Mito M, Khan K, Dohmae N, Iwasaki S, Yoshida M.
|
| Title |
Splicing modulators elicit global translational repression by condensate-prone proteins translated from introns.
|
| Journal |
Cell Chem Biol
|
| 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.
|
| Volume |
29(2)
|
| Pages |
259-275.e10
|
| Published |
2022-2-17
|
| DOI |
10.1016/j.chembiol.2021.07.015
|
| PII |
S2451-9456(21)00355-X
|
| PMID |
34520743
|
| PMC |
PMC8857039
|
| MeSH |
Cell Line
Enzyme Inhibitors / pharmacology
Humans
Introns
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases / genetics*
Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
Mechanistic Target of Rapamycin Complex 1 / genetics*
Pyrans / pharmacology
RNA Splicing / drug effects
RNA Splicing / genetics*
RNA-Seq
Spiro Compounds / pharmacology
Spliceosomes / drug effects
Spliceosomes / genetics*
|
| IF |
6.762
|
| Resource |
| Human and Animal Cells |
HeLa.S3(RCB1525) |
