TREX1 Deficiency Induces ER Stress-Mediated Neuronal Cell Death by Disrupting Ca2+ Homeostasis

TREX1 is an exonuclease that degrades extranuclear DNA species in mammalian cells. Herein, we show a novel mechanism by which TREX1 interacts with the BiP/GRP78 and TREX1 deficiency triggers ER stress through the accumulation of single-stranded DNA and activates unfolded protein response (UPR) signa...

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Published in:Molecular neurobiology 2022-03, Vol.59 (3), p.1398-1418
Main Authors: Halder, Debasish, Jeon, Su-Jin, Yoon, Ji-Yong, Lee, Jeong-Ju, Jun, Soo Young, Choi, Min-Hyuk, Jeong, Bohyeon, Sung, Duk Hyun, Lee, Da Yong, Kim, Byoung Joon, Kim, Nam-Soon
Format: Article
Language:English
Subjects:
Apoptosis
Biomedical and Life Sciences
Biomedicine
Ca2+/calmodulin-dependent protein kinase II
Calcium homeostasis
Calcium signalling
Cell activation
Cell Biology
Cell death
Exonuclease
Golgi apparatus
Hereditary spastic paraplegia
Homeostasis
Mammalian cells
Mutation
Neurobiology
Neurodegenerative diseases
Neurology
Neurosciences
Protein folding
Single-stranded DNA
Spasticity
Therapeutic targets
Tubulin
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Summary:TREX1 is an exonuclease that degrades extranuclear DNA species in mammalian cells. Herein, we show a novel mechanism by which TREX1 interacts with the BiP/GRP78 and TREX1 deficiency triggers ER stress through the accumulation of single-stranded DNA and activates unfolded protein response (UPR) signaling via the disruption of the TREX1-BiP/GRP78 interaction. In TREX1 knockdown cells, the activation of ER stress signaling disrupted ER Ca 2+ homeostasis via the ERO1α-IP3R1-CaMKII pathway, leading to neuronal cell death. Moreover, TREX1 knockdown dysregulated the Golgi-microtubule network through Golgi fragmentation and decreased Ac-α-tubulin levels, contributing to neuronal injury. These alterations were also observed in neuronal cells harboring a TREX1 mutation (V91M) that has been identified in hereditary spastic paraplegia (HSP) patients in Korea. Notably, this mutation leads to defects in the TREX1-BiP/GRP78 interaction and mislocalization of TREX1 from the ER and possible disruption of the Golgi-microtubule network. In summary, the current study reveals TREX1 as a novel regulator of the BiP/GRP78 interaction and shows that TREX1 deficiency promotes ER stress-mediated neuronal cell death, which indicates that TREX1 may hold promise as a therapeutic target for neurodegenerative diseases such as HSP.
ISSN:0893-7648
1559-1182
DOI:10.1007/s12035-021-02631-3