2. Academic Validation
  3. Congress of multiple dimers is needed for cross-phosphorylation of IRE1α and its RNase activity

Congress of multiple dimers is needed for cross-phosphorylation of IRE1α and its RNase activity

  • Life Sci Alliance. 2024 Jun 17;7(9):e202302562. doi: 10.26508/lsa.202302562.
Andrea Orsi 1,  Eelco van Anken 2,  Milena Vitale 2,  Moreno Zamai 3,  Valeria R Caiolfa 3 4,  Roberto Sitia 5,  Anush Bakunts 6
Affiliations

Affiliations

  • 1 Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 2 https://ror.org/01gmqr298 Division of Genetics and Cell Biology, Vita-Salute San Raffaele University, Milan, Italy.
  • 3 Unit of Microscopy and Dynamic Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 4 Center for Experimental Imaging, IRCCS Ospedale San Raffaele, Milan, Italy.
  • 5 https://ror.org/01gmqr298 Division of Genetics and Cell Biology, Vita-Salute San Raffaele University, Milan, Italy sitia.roberto@hsr.it.
  • 6 https://ror.org/01gmqr298 Division of Genetics and Cell Biology, Vita-Salute San Raffaele University, Milan, Italy bakunts.anush@hsr.it.
PMID: 38886017 DOI: 10.26508/lsa.202302562
Abstract

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.

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