Figure 7. Model for Ire1α-mediated cleavage of ER-localized mRNAs.
Ire1α forms a complex with the Sec61 translocon, to which XBP1u mRNA is recruited by its ribosome nascent chains (RNCs) through the SRP pathway. Despite interacting with the Sec61 translocon, the XBP1u nascent chain is inefficiently inserted into the ER membrane due to its weak hydrophobic region. Upon ER stress, Ire1α is activated through self-oligomerization and cleaves XBP1u mRNA to yield an active transcription factor, XBP1s, as well as to cleave ER-localized mRNAs through regulated Ire1-dependent decay (RIDD).