DELE1
Domain
The TPR repeats bind to and activate EIF2AK1/HRI.
Function
Protein kinase activator that acts as a key activator of the integrated stress response (ISR) following various stresses, such as iron deficiency, mitochondrial stress or mitochondrial DNA breaks (PubMed:32132706, PubMed:32132707, PubMed:35388015, PubMed:37327776, PubMed:37550454, PubMed:37832546, PubMed:38340717). Detects impaired protein import and processing in mitochondria, activating the ISR (PubMed:35388015). May also required for the induction of death receptor-mediated apoptosis through the regulation of caspase activation (PubMed:20563667).
DAP3-binding cell death enhancer 1
Protein kinase activator that activates the ISR in response to iron deficiency: iron deficiency impairs mitochondrial import, promoting DELE1 localization at the mitochondrial surface, where it binds and activates EIF2AK1/HRI to trigger the ISR.
DAP3-binding cell death enhancer 1 short form
Protein kinase activator generated by protein cleavage in response to mitochondrial stress, which accumulates in the cytosol and specifically binds to and activates the protein kinase activity of EIF2AK1/HRI (PubMed:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:37832546, PubMed:38340717). It thereby activates the integrated stress response (ISR): EIF2AK1/HRI activation promotes eIF-2-alpha (EIF2S1) phosphorylation, leading to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, the master transcriptional regulator of the ISR (PubMed:32132706, PubMed:32132707, PubMed:37327776, PubMed:37550454, PubMed:37832546). Also acts as an activator of PRKN-independent mitophagy: activates the protein kinase activity of EIF2AK1/HRI in response to mitochondrial damage, promoting eIF-2-alpha (EIF2S1) phosphorylation, leading to mitochondrial localization of EIF2S1 followed by induction of mitophagy (PubMed:38340717).
Post-translational modifications
DAP3-binding cell death enhancer 1
Unstable protein in absence of stress: imported in the mitochondrial matrix following processing by the mitochondrial-processing peptidase (MPP), where it is degraded by LONP1 (PubMed:37327776). Stabilized in response to iron deficiency: iron deficiency impairs mitochondrial import, promoting localization at the mitochondrial surface and stabilization (PubMed:37327776). Cleaved by OMA1 in response to mitochondrial stress, generating the DAP3-binding cell death enhancer 1 short form (DELE1(S) or S-DELE1) that accumulates in the cytosol and activates the protein kinase activity of EIF2AK1/HRI (PubMed:32132706, PubMed:32132707, PubMed:37327776, PubMed:38340717). Protein cleavage by OMA1 can take place at different positions, and apparently does not require a specific sequence motif (PubMed:32132707).
DAP3-binding cell death enhancer 1 short form
Ubiquitinated and degraded by the SIFI complex once the mitochondrial stress has been resolved, thereby providing stress response silencing (PubMed:38297121). Within the SIFI complex, UBR4 initiates ubiquitin chain that are further elongated or branched by KCMF1 (PubMed:38297121).
Sequence Similarities
Belongs to the DELE1 family.
Tissue Specificity
Detected in liver, skeletal muscle, kidney, pancreas, spleen, thyroid, testis, ovary, small intestine and colon.
Cellular localization
- DAP3-binding cell death enhancer 1
- Mitochondrion
- Mitochondrion outer membrane
- Mitochondrion inner membrane
- Imported in the mitochondrial matrix in absence of stress, leading to its degradation by LONP1 (PubMed:37327776). Localizes at the mitochondrial surface in response to iron deficiency: iron deficiency impairs mitochondrial import, promoting localization at the mitochondrial surface and stabilization (PubMed:37327776). Associates with the mitochondrion inner membrane in response to mitochondrial stress, leading to its proteolytic processing by OMA1, and generation of the AP3-binding cell death enhancer 1 short form (DELE1(S) or S-DELE1) (PubMed:32132707).
- DAP3-binding cell death enhancer 1 short form
- Cytoplasm
- Cytosol
- This short form is generated by proteolytic processing by OMA1 in response to mitochondrial stress, leading to translocation to the cytosol.
Alternative names
DELE, KIAA0141, DELE1, DAP3-binding cell death enhancer 1, Death ligand signal enhancer, DELE1(L)