TREX1 Deficiency Induces ER Stress-Mediated Neuronal Cell Death by Disrupting Ca 2+ 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 inMolecular neurobiology Vol. 59; no. 3; p. 1398
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 Journal Article
LanguageEnglish
Published United States 01.03.2022
Subjects
Animals
Cell Death
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum Chaperone BiP
Heat-Shock Proteins - genetics
Heat-Shock Proteins - metabolism
Homeostasis
Humans
Mammals - metabolism
Ca2+ homeostasis
Hereditary spastic paraplegia
Neuronal cells
BiP/GRP78
ER stress
Three prime repair exonuclease 1
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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 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:1559-1182