RT Journal Article
SR Electronic
T1 Splicing modulators elicit global translational repression by condensate-prone proteins translated from introns
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.23.393835
DO 10.1101/2020.11.23.393835
A1 Shrestha, Jagat Krishna Chhipi
A1 Schneider-Poetsch, Tilman
A1 Suzuki, Takehiro
A1 Mito, Mari
A1 Khan, Khalid
A1 Dohmae, Naoshi
A1 Iwasaki, Shintaro
A1 Yoshida, Minoru
YR 2020
UL http://biorxiv.org/content/early/2020/11/23/2020.11.23.393835.abstract
AB Chemical splicing modulators that bind to the spliceosome have provided an attractive venue for cancer treatment. Splicing modulators induce accumulation and subsequent translation of a subset of intron-retained mRNAs. Yet, the biological effect of proteins containing translated intron sequences remains unclear. Here we identified a number of truncated proteins generated upon treatment with the splicing modulator spliceostatin A (SSA) using genome-wide ribosome profiling and bio-orthogonal non-canonical 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 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.Competing Interest StatementThe authors have declared no competing interest.