IRE1α is an essential regulator for unconventional secretion of CFTR via its kinase activity

[Speaker] He Piao:1
[Co-author] Min Goo Lee:1
1:Department of Pharmacology, Yonsei University College of Medicine, Korea

CFTR is a transmembrane anion channel that travels to the cell surface via the Golgi-mediated conventional secretion pathway. Previously, we identified that ER stress or ER-to-Golgi block could rescue the disease-causing mutant ΔF508-CFTR, which has folding and trafficking defects, from degradation to reach the cell surface through GRASP-mediated, Golgi bypassing unconventional secretion pathway. We showed that IRE1α mediated signaling plays as an upstream regulator during unconventional secretion of CFTR. IRE1α is one of the three major ER-stress sensors of UPR (Unfolded protein response) signaling which is an adaptive mechanism to maintain ER homeostasis. Classically, ER-stress triggers activation of IRE1α RNase and results in excising of transcription factor XBP1 into activated XBP1s(spliced) to upregulate UPR target genes. However, depletion of XBP1 does not abolish the ER-to-Golgi block or ER stress induced surface expression of ΔF508-CFTR. Interestingly, we show that inhibition of IRE1α RNase activity by treatment of STF-083010 targeting to catalytic core of IRE1α RNase domain does not interfere the unconventional secretion of CFTR. Whereas treatment of IRE1α kinase inhibitor APY29 which inhibits IRE1α trans-autophosphorylation leads to diminishment of ER-to-Golgi block induced surface expression of ΔF508-CFTR. Notably, the IRE1α pharmacological modulation results reveal that the kinase activity but not RNase activity of IRE1α is requisite for regulation of unconventional secretion of CFTR.
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