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Chemically-induced degradation of the endoplasmic-reticulum 1 stress sensor IRE1 2 by a VHL-recruiting chimera

ABSTRACT: The endoplasmic-reticulum (ER) transmembrane protein IRE1 mitigates ER stress through kinase-ribonuclease (KR) and scaffolding activities. Cancer cells often co-opt IRE1 to facilitate growth. An IRE1-RNase inhibitor has entered clinical trials; however, recent work uncovered a significant nonenzymatic IRE1 dependency in cancer. To fully disrupt IRE1, we designed a proteolysis-targeting chimera (G6374) that couples an IRE1-kinase ligand to a compound that binds the ubiquitin Cullin RING Ligase (CRL) adapter VHL. G6374 induced stable interaction between IRE1 and VHL, driving VHL-dependent IRE1 K48-linked ubiquitination on two principal kinase sites and inducing proteasomal IRE1 degradation. Cryogenic electron microscopy and mutational studies revealed a 2:2 IRE1:VHL ternary-complex topology and critical interactional features, informing future designs. G6374 blocked growth of IRE1-dependent cancer cells irrespective of their dependency mode, while sparing IRE1-independent cells. We provide the first proof-of-concept for VHL-based degradation of an ER-transmembrane protein, advancing strategies to fully disrupt IRE1.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Christopher M. Rose

PROVIDER: MSV000097222 | MassIVE | Mon Mar 03 17:16:00 GMT 2025

REPOSITORIES: MassIVE

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