TREX1 Deficiency Induces ER Stress-Mediated Neuronal Cell Death by Disrupting Ca 2+ Homeostasis.

Autor: Halder D; Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141, Daejeon, Republic of Korea.; Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141, Daejeon, Republic of Korea., Jeon SJ; Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141, Daejeon, Republic of Korea.; Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141, Daejeon, Republic of Korea.; Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, 34113, Daejeon, Republic of Korea., Yoon JY; Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141, Daejeon, Republic of Korea.; Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141, Daejeon, Republic of Korea., Lee JJ; Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141, Daejeon, Republic of Korea.; Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141, Daejeon, Republic of Korea., Jun SY; Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141, Daejeon, Republic of Korea.; Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141, Daejeon, Republic of Korea., Choi MH; Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141, Daejeon, Republic of Korea.; Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141, Daejeon, Republic of Korea.; Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, 34113, Daejeon, Republic of Korea., Jeong B; Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141, Daejeon, Republic of Korea., Sung DH; Department of Physical and Rehabilitation Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, 06351, Seoul, Republic of Korea., Lee DY; Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141, Daejeon, Republic of Korea., Kim BJ; Department of Neurology, Sungkyunkwan University School of Medicine, Samsung Medical Center, 06351, Seoul, Republic of Korea., Kim NS; Rare Disease Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 34141, Daejeon, Republic of Korea. nskim37@kribb.re.kr.; Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141, Daejeon, Republic of Korea. nskim37@kribb.re.kr.; Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, 34113, Daejeon, Republic of Korea. nskim37@kribb.re.kr.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2022 Mar; Vol. 59 (3), pp. 1398-1418. Date of Electronic Publication: 2022 Jan 07.
DOI: 10.1007/s12035-021-02631-3
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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