Caspase-mediated cleavage of IRE1 controls apoptotic cell commitment during endoplasmic reticulum stress.

Abstract:

:Upon detecting endoplasmic reticulum (ER) stress, the unfolded protein response (UPR) orchestrates adaptive cellular changes to reestablish homeostasis. If stress resolution fails, the UPR commits the cell to apoptotic death. Here we show that in hematopoietic cells, including multiple myeloma (MM), lymphoma, and leukemia cell lines, ER stress leads to caspase-mediated cleavage of the key UPR sensor IRE1 within its cytoplasmic linker region, generating a stable IRE1 fragment comprising the ER-lumenal domain and transmembrane segment (LDTM). This cleavage uncouples the stress-sensing and signaling domains of IRE1, attenuating its activation upon ER perturbation. Surprisingly, LDTM exerts negative feedback over apoptotic signaling by inhibiting recruitment of the key proapoptotic protein BAX to mitochondria. Furthermore, ectopic LDTM expression enhances xenograft growth of MM tumors in mice. These results uncover an unexpected mechanism of cross-regulation between the apoptotic caspase machinery and the UPR, which has biologically significant consequences for cell survival under ER stress.

journal_name

Elife

journal_title

eLife

authors

Shemorry A,Harnoss JM,Guttman O,Marsters SA,Kőműves LG,Lawrence DA,Ashkenazi A

doi

10.7554/eLife.47084

subject

Has Abstract

pub_date

2019-08-27 00:00:00

issn

2050-084X

pii

47084

journal_volume

8

pub_type

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