TREX1 deficiency induces ER stress-mediated neuronal cell death by disrupting Ca 2+ homeostasis

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Title
TREX1 deficiency induces ER stress-mediated neuronal cell death by disrupting Ca 2+ homeostasis
Author(s)
Debasish Halder; Su Jin Jeon; Ji Yong YoonJeong Ju Lee; Soo Young Jun; Min Hyuk Choi; Bohyeon Jeong; D H Sung; Da Yong Lee; B J Kim; Nam-Soon Kim
Bibliographic Citation
Molecular Neurobiology, vol. 59, no. 3, pp. 1398-1418
Publication Year
2022
Abstract
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 Ca2+ 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.
Keyword
Three prime repair exonuclease 1ER stressBiP/GRP78Ca2+ homeostasisNeuronal cellsHereditary spastic paraplegia
ISSN
0893-7648
Publisher
Springer
DOI
http://dx.doi.org/10.1007/s12035-021-02631-3
Type
Article
Appears in Collections:
Division of Biomedical Research > Rare Disease Research Center > 1. Journal Articles
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