Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α promotes cancer-cell survival

Le Thomas, A.; Ferri, E.; Marsters, S.; Harnoss, J. M.; Modrusan, Z.; Li, W.; Rudolph, J.; Wang, W.; Wu, T. D.; Walter, P.; Ashkenazi, A.

doi:10.1101/2021.03.16.435520

bioRxiv · 10.1101/2021.03.16.435520

Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α promotes cancer-cell survival

Le Thomas, A.·Ferri, E.·Marsters, S.·Harnoss, J. M.·Modrusan, Z.·Li, W.·Rudolph, J.·Wang, W.·Wu, T. D.·Walter, P.·Ashkenazi, A.

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Abstract

Eukaryotic IRE1 mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, mammalian RIDD seemingly targets only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1-controlled mRNAs in human breast cancer cells, we discovered not only canonical endomotif-containing RIDD substrates, but also many targets lacking recognizable motifs--degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1 displayed two basic endoribonuclease modalities: endomotif-specific cleavage, minimally requiring dimers; and endomotif-independent promiscuous processing, requiring phospho-oligomers. An oligomer-deficient mutant that did not support RIDDLE failed to rescue cancer-cell viability. These results link IRE1 oligomers, RIDDLE, and cell survival, advancing mechanistic understanding of the UPR.

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Le Thomas, A., Ferri, E., Marsters, S., Harnoss, J. M., Modrusan, Z., Li, W., Rudolph, J., Wang, W., Wu, T. D., Walter, P., Ashkenazi, A.. 2021-03-16. Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α promotes cancer-cell survival. https://doi.org/10.1101/2021.03.16.435520

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