2. Academic Validation
  3. ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR

ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR

  • Nat Chem Biol. 2021 Nov;17(11):1148-1156. doi: 10.1038/s41589-021-00852-0.
Hannah C Feldman 1,  Rajarshi Ghosh 2 3 4 5 6,  Vincent C Auyeung 2 3 4 5 6,  James L Mueller 2 7,  Jae-Hong Kim 2 3 4 5 6,  Zachary E Potter 1,  Venkata N Vidadala 1,  B Gayani K Perera 1,  Alina Olivier 2 3 4 5 6,  Bradley J Backes 2 3,  Julie Zikherman 2 7,  Feroz R Papa 8 9 10 11 12,  Dustin J Maly 13 14
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Washington, Seattle, WA, USA.
  • 2 Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • 3 Lung Biology Center, University of California, San Francisco, San Francisco, CA, USA.
  • 4 Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • 5 Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
  • 6 Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA.
  • 7 Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, University of California, San Francisco, San Francisco, CA, USA.
  • 8 Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. feroz.papa@ucsf.edu.
  • 9 Lung Biology Center, University of California, San Francisco, San Francisco, CA, USA. feroz.papa@ucsf.edu.
  • 10 Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. feroz.papa@ucsf.edu.
  • 11 Diabetes Center, University of California, San Francisco, San Francisco, CA, USA. feroz.papa@ucsf.edu.
  • 12 Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA. feroz.papa@ucsf.edu.
  • 13 Department of Chemistry, University of Washington, Seattle, WA, USA. djmaly@uw.edu.
  • 14 Department of Biochemistry, University of Washington, Seattle, WA, USA. djmaly@uw.edu.
PMID: 34556859 DOI: 10.1038/s41589-021-00852-0
Abstract

The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. However, under high or chronic ER stress, the UPR triggers Apoptosis. This cell fate dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1α. We previously found that the RNase of IRE1α can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors, partial antagonists of IRE1α RNase (PAIRs), that partially antagonize the IRE1α RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the helix αC in the IRE1α kinase domain. In insulin-producing β-cells, PAIRs permit adaptive splicing of Xbp1 mRNA while quelling destructive ER mRNA endonucleolytic decay and Apoptosis. By preserving Xbp1 mRNA splicing, PAIRs allow B cells to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory 'sweet spot', achieved by PAIR-bound IRE1α, captures a desirable conformation for drugging this master UPR sensor/effector.

Figures
Products