| 2020 |
DELE1 is associated with the inner mitochondrial membrane under steady-state conditions; mitochondrial stress (e.g., membrane depolarization) activates the OMA1 protease, which cleaves DELE1; the resulting short form accumulates in the cytosol where it directly interacts with and activates the eIF2α kinase HRI, triggering the integrated stress response (ISR) and ATF4 translation. |
Genome-wide CRISPR interference screen, co-immunoprecipitation, subcellular fractionation, in vitro kinase assays, loss-of-function (siRNA/CRISPRi) with defined eIF2α phosphorylation and ATF4 induction readouts |
Nature |
High |
32132706 32132707
|
| 2020 |
The C-terminal portion of DELE1 is sufficient to bind and activate HRI in the cytosol; stress-induced OMA1-dependent cleavage generates a short DELE1 form that accumulates in the cytosol and engages HRI via its C-terminal region. |
Domain-mapping experiments, truncation constructs, Co-IP, functional ISR activation assays in haploid cells and mammalian cells |
Nature |
High |
32132706 32132707
|
| 2022 |
DELE1 is continuously imported across both mitochondrial membranes into the matrix, surveying diverse perturbations along the import route. Proteolytic removal of N-terminal sorting signals licenses DELE1 molecules in transit for mitochondrial release and stress signaling. Import defects at the mitochondrial surface allow unprocessed DELE1 precursors to bind and activate HRI directly, without the need for OMA1-mediated cleavage. Matrix proteases PITRM1 and MPP also regulate DELE1 activation by controlling presequence processing. |
Genome-wide genetic screens, subcellular fractionation, import assays, mutational analysis of sorting signals, loss-of-function knockouts of PITRM1/MPP |
Nature communications |
High |
35388015
|
| 2023 |
The cryo-EM structure of the C-terminal cleavage product of human DELE1 reveals it assembles into a high-order octameric complex with D4 symmetry via two sets of hydrophobic inter-subunit interactions. Mutagenesis of key oligomerization residues disrupts octamer formation in vitro and in cells, and assembly-impaired mutants are compromised in their ability to activate HRI-dependent ISR signaling. |
Cryo-electron microscopy structure determination, site-directed mutagenesis, in vitro reconstitution of oligomer assembly, cell-based ISR activation assays |
Nature structural & molecular biology |
High |
37550454
|
| 2023 |
Under iron-deficient conditions, DELE1 mitochondrial import is arrested, stabilizing DELE1 on the mitochondrial surface to activate HRI-mediated ISR. Under steady-state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 shortly after import, limiting basal signaling. Iron chelation blocks LONP1-dependent degradation by preventing complete import. |
Iron chelation experiments, LONP1 knockout/knockdown, DELE1 import and stability assays, flow cytometry-based cell death assays in erythroid cell models |
Molecular cell |
High |
37327776
|
| 2010 |
DELE1 (originally called DELE) was identified as a direct binding partner of DAP3 (death-associated protein 3). Stable overexpression of DELE1 sensitizes cells to TNF-α- and TRAIL-induced apoptosis, and knockdown of DELE1 rescues cells from apoptosis by these stimuli and inhibits caspase-3, -8, and -9 activation. |
Yeast two-hybrid screening, co-immunoprecipitation in mammalian cells, stable overexpression, siRNA knockdown with caspase activation readouts |
Apoptosis |
Medium |
20563667
|
| 2024 |
Mitochondrial protein import stress (MPIS) is an overarching stress that triggers DELE1 cleavage and HRI activation. Endogenous DELE1 can be cleaved into two forms: DELE1-S (generated under depolarizing stress) and DELE1-VS (generated only under non-depolarizing MPIS). The mitochondrial protease HtrA2 mediates DELE1 cleavage into DELE1-VS; a Parkinson's disease-associated HtrA2 mutant displays reduced DELE1 processing. OMA1 is required for DELE1 cleavage in HeLa cells but is dispensable in HEK293T cells, indicating cell-type-specific protease usage. |
Endogenous DELE1 detection by western blot, siRNA knockdown of OMA1 and HtrA2 in multiple cell lines, overexpression of PD-associated HtrA2 mutants, DELE1 cleavage assays |
Communications biology |
Medium |
38555279
|
| 2024 |
The ISR mediated by DELE1-HRI suppresses PINK1-dependent mitophagy under non-depolarizing mitochondrial stress by positively regulating mitochondrial protein import efficiency, independent of ATF4 activation. Without ISR, increased protein synthesis overwhelms the import machinery, reducing efficiency and enabling PINK1 accumulation to trigger mitophagy. |
DELE1/HRI loss-of-function, PINK1 accumulation assays, protein import efficiency measurements, ATF4-independent pathway analysis |
bioRxivpreprint |
Medium |
|
| 2025 |
Prohibitins (PHBs) regulate DELE1 localization at the inner mitochondrial membrane; targeting PHBs (by fluorizoline treatment or knockdown) impairs the mitochondrial protein import pre-sequence pathway and causes accumulation of DELE1 outside mitochondria, activating ISR via DELE1-HRI. OMA1 is dispensable for ISR activation following PHB targeting, distinguishing this from canonical depolarization-induced DELE1 cleavage. |
Fluorizoline treatment, PHB siRNA knockdown, DELE1 localization by fractionation, OMA1 knockout/knockdown, ISR activation assays in HeLa and HAP1 cells |
Cell death and differentiation |
Medium |
41291210
|
| 2026 |
De novo designed protein binders engage a critical oligomerization interface on DELE1, block DELE1 oligomerization in vitro while preserving DELE1's ability to bind HRI, and suppress ATF4 induction and ISR activation during mitochondrial stress in cells. A crystal structure of a representative binder confirms engagement of the oligomerization interface, validated by mutagenesis. |
De novo protein design, in vitro binding and oligomerization assays, crystal structure determination, mutagenesis, cell-based ISR activation (ATF4) assays, mitochondrial morphology imaging |
bioRxivpreprint |
Medium |
41717097
|
| 2022 |
In ovarian cancer cells, OMA1 activation leads to DELE1 cleavage and cytoplasmic interaction of cleaved DELE1 with EIF2AK1 (HRI), which cooperates with ER stress sensor EIF2AK3 to amplify the EIF2S1/ATF4 signal and promote apoptosis. PHB2/STOML2 complex regulates OMA1 protease activity upstream of DELE1. |
OMA1 knockdown, cisplatin treatment in cells and mouse xenograft models, western blot for DELE1 cleavage and EIF2S1/ATF4, Co-IP for DELE1-EIF2AK1 interaction |
International journal of molecular sciences |
Medium |
35163244
|