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

Debasish Halder,Da Yong Lee,Min-Hyuk Choi,Byoung Joon Kim,Su-Jin Jeon,Ji-Yong Yoon,Bohyeon Jeong,Duk Hyun Sung,Nam-Soon Kim,Jeong-Ju Lee,Soo Young Jun

doi:10.1007/s12035-021-02631-3

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.

Highlights

Three prime repair exonuclease 1 (TREX1) is a major 3′ DNA exonuclease that degrades single- and double-stranded DNA polymers in mammalian cells
The results showed that TREX1 knockdown inhibited the expression of neuronal markers compared to that of control cells (Fig. 1A–C)
TREX1-silenced neuronal cells treated with nucleoside analog reverse transcriptase inhibitors (RTis) [5, 23] lamivudine (3TC) and stavudine (d4T) were relatively healthier with longer neurites than TREX1-silenced cells that were not treated with a RTi (Fig. 1A; bottom panel and Fig. 1B and 1C; right panel)

Summary

Introduction

Three prime repair exonuclease 1 (TREX1) is a major 3′ DNA exonuclease that degrades single- and double-stranded DNA polymers in mammalian cells. The N-terminal catalytic domain (242 amino acids) of TREX1 acts on extranuclear DNA species to prevent self-DNA from activating the interferon response. The C-terminal 72 amino acids contain a hydrophobic region that localizes TREX1 to the endoplasmic reticulum (ER) in the perinuclear space of cells and plays an essential role in protein folding/biosynthesis [1,2,3,4]. The major role of TREX1 is degradation of singlestranded DNA (ssDNA) that is derived from endogenous retroelements and HIV DNA that is generated during HIV-1 infection, thereby preventing activation of the cell-intrinsic autoimmune pathway.

Methods

Results

Conclusion