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
Human and Animal Cells HeLa.S3(RCB1525)