Structural Basis for Activation of HRI by the DELE1 C-terminal domain
- 1University of Dundee
Abstract
Haem-Regulated Inhibitor (HRI, aka EIF2AK1) is one of four stress-sensing kinases that phosphorylate eIF2 as part of the integrated stress response (ISR). HRI was first characterized as a haem-sensing kinase where it is inhibited when bound to haem. Recent studies have revealed another role for HRI in sensing mitochondrial stress via the mitochondrial protein DELE1. Upon stress, DELE1 is cleaved, and its C-terminal fragment (DELE1CTD) is released from the mitochondria to the cytoplasm, where it interacts with HRI, to trigger the ISR. This pathway is critical for mitochondrial quality control and neuronal health. Here, we perform biophysical analysis to demonstrate that purified recombinant DELE1CTD binds with high affinity to the N-terminal region of HRI, competing with and displacing haem to activate HRI and pointing to a shared binding site. Using Hydrogen Deuterium Exchange Mass Spectrometry (HDX-MS), we map the binding footprint of DELE1CTD on HRI and confirm that it overlaps with the haem-binding site. These findings support a simple activation mechanism: DELE1CTD activates HRI by excluding inhibitory haem from its binding site.
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BibTeX
@misc{raimi2026structural,
title = {{Structural Basis for Activation of HRI by the DELE1 C-terminal domain}},
author = {O. G. Raimi and R. Bhattacharjee and M. Cao and S. Richardson and A. C. H. Liu and V. Vinciauskaite and C. de Marcos Lousa and M. M. K. Muqit and G. R. Masson},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751698},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751698v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Structural Basis for Activation of HRI by the DELE1 C-terminal domain
AU - O. G. Raimi
AU - R. Bhattacharjee
AU - M. Cao
AU - S. Richardson
AU - A. C. H. Liu
AU - V. Vinciauskaite
AU - C. de Marcos Lousa
AU - M. M. K. Muqit
AU - G. R. Masson
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751698
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751698v1
AB - Haem-Regulated Inhibitor (HRI, aka EIF2AK1) is one of four stress-sensing kinases that phosphorylate eIF2 as part of the integrated stress response (ISR). HRI was first characterized as a haem-sensing kinase where it is inhibited when bound to haem. Recent studies have revealed another role for HRI in sensing mitochondrial stress via the mitochondrial protein DELE1. Upon stress, DELE1 is cleaved, and its C-terminal fragment (DELE1CTD) is released from the mitochondria to the cytoplasm, where it interacts with HRI, to trigger the ISR. This pathway is critical for mitochondrial quality control and neuronal health. Here, we perform biophysical analysis to demonstrate that purified recombinant DELE1CTD binds with high affinity to the N-terminal region of HRI, competing with and displacing haem to activate HRI and pointing to a shared binding site. Using Hydrogen Deuterium Exchange Mass Spectrometry (HDX-MS), we map the binding footprint of DELE1CTD on HRI and confirm that it overlaps with the haem-binding site. These findings support a simple activation mechanism: DELE1CTD activates HRI by excluding inhibitory haem from its binding site.
ER -