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

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.

PPP1R3A inhibits osteogenesis and negatively regulates intracellular calcium levels in calcific tendinopathy

“… 21 Interruption of Ca2+ homeostasis in the ER leads to activation of ER stress-coping responses, for instance, the unfolded protein response (UPR). 22 The accumulated evidence suggests that constant interrupting Ca2+ homeostasis and chronic ER stress could lead to kidney disease, 23 neurodegenerative disorders, 24 or cancer. 25 PPP1R3A mediates PP1c regulation of both RyR2 and PLN within an extended RyR2/PLN/SERCA2a complex that as joint Ca2+ release/re-uptake regulatome complexes.…”