RT Journal Article
SR Electronic
T1 Congress of multiple dimers is needed for cross-phosphorylation of IRE1α and its RNase activity
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202302562
DO 10.26508/lsa.202302562
VO 7
IS 9
A1 Orsi, Andrea
A1 van Anken, Eelco
A1 Vitale, Milena
A1 Zamai, Moreno
A1 Caiolfa, Valeria R
A1 Sitia, Roberto
A1 Bakunts, Anush
YR 2024
UL https://www.life-science-alliance.org/content/7/9/e202302562.abstract
AB The unfolded protein response can switch from a pro-survival to a maladaptive, pro-apoptotic mode. During ER stress, IRE1α sensors dimerize, become phosphorylated, and activate XBP1 splicing, increasing folding capacity in the ER protein factory. The steps that turn on the IRE1α endonuclease activity against endogenous mRNAs during maladaptive ER stress are still unknown. Here, we show that although necessary, IRE1α dimerization is not sufficient to trigger phosphorylation. Random and/or guided collisions among IRE1α dimers are needed to elicit cross-phosphorylation and endonuclease activities. Thus, reaching a critical concentration of IRE1α dimers in the ER membrane is a key event. Formation of stable IRE1α clusters is not necessary for RNase activity. However, clustering could modulate the potency of the response, promoting interactions between dimers and decreasing the accessibility of phosphorylated IRE1α to phosphatases. The stepwise activation of IRE1α molecules and their low concentration at the steady state prevent excessive responses, unleashing full-blown IRE1 activity only upon intense stress conditions.