XBP1-KLF9 Axis Acts as a Molecular Rheostat to Control the Transition from Adaptive to Cytotoxic Unfolded Protein Response.

Abstract:

:Transcription factor XBP1s, activated by endoplasmic reticulum (ER) stress in a dose-dependent manner, plays a central role in adaptive unfolded protein response (UPR) via direct activation of multiple genes controlling protein refolding. Here, we report that elevation of ER stress above a critical threshold causes accumulation of XBP1s protein sufficient for binding to the promoter and activation of a gene encoding a transcription factor KLF9. In comparison to other XBP1s targets, KLF9 promoter contains an evolutionary conserved lower-affinity binding site that requires higher amounts of XBP1s for activation. In turn, KLF9 induces expression of two regulators of ER calcium storage, TMEM38B and ITPR1, facilitating additional calcium release from ER, exacerbation of ER stress, and cell death. Accordingly, Klf9 deficiency attenuates tunicamycin-induced ER stress in mouse liver. These data reveal a role for XBP1s in cytotoxic UPR and provide insights into mechanisms of life-or-death decisions in cells under ER stress.

journal_name

Cell Rep

journal_title

Cell reports

authors

Fink EE,Moparthy S,Bagati A,Bianchi-Smiraglia A,Lipchick BC,Wolff DW,Roll MV,Wang J,Liu S,Bakin AV,Kandel ES,Lee AH,Nikiforov MA

doi

10.1016/j.celrep.2018.09.013

subject

Has Abstract

pub_date

2018-10-02 00:00:00

pages

212-223.e4

issue

1

issn

2211-1247

pii

S2211-1247(18)31443-8

journal_volume

25

pub_type

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