ER-directed TREX1 limits cGAS activation at micronuclei Journal Article

   


Authors: Mohr, L.; Toufektchan, E.; von Morgen, P.; Chu, K.; Kapoor, A.; Maciejowski, J.
Article Title: ER-directed TREX1 limits cGAS activation at micronuclei
Abstract: The ER-associated nuclease TREX1 guards against immune disease by clearing immunostimulatory DNA from the cytosol. Mohr et al. identify a key role for the ER in limiting immune activation by directing TREX1 engagement with DNA substrates such as micronuclei. © 2020 Elsevier Inc. Micronuclei are aberrant nuclear compartments that can form as a result of chromosome mis-segregation. Frequent loss of micronuclear envelope integrity exposes DNA to the cytoplasm, leading to chromosome fragmentation and immune activation. Here, we use micronuclei purification to show that the endoplasmic reticulum (ER)-associated nuclease TREX1 inhibits cGAS activation at micronuclei by degrading micronuclear DNA upon micronuclear envelope rupture. We demonstrate that the ER accesses ruptured micronuclei and plays a critical role in enabling TREX1 nucleolytic attack. TREX1 mutations, previously implicated in immune disease, untether TREX1 from the ER, disrupt TREX1 localization to micronuclei, diminish micronuclear DNA damage, and enhance cGAS activation. These results establish ER-directed resection of micronuclear DNA by TREX1 as a critical regulator of cytosolic DNA sensing in chromosomally unstable cells and provide a mechanistic basis for the importance of TREX1 ER tethering in preventing autoimmunity. © 2020 Elsevier Inc.
Keywords: endoplasmic reticulum; chromosome instability; nuclear envelope; chromothripsis; sting; cgas; trex1; ape1; baf; micronuclei
Journal Title: Molecular Cell
Volume: 81
Issue: 4
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2021-02-18
Start Page: 724
End Page: 738.e9
Language: English
DOI: 10.1016/j.molcel.2020.12.037
PUBMED: 33476576
PROVIDER: scopus
PMCID: PMC7897315
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85100651110&doi=10.1016%2fj.molcel.2020.12.037&partnerID=40&md5=43a41ea6dbfbdc0fd836798813c0e89e
Notes: Article -- Export Date: 1 March 2021 -- Source: Scopus
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MSK Authors
  1. John Maciejowski
    32 Maciejowski
  2. Patrick Joel Von Morgen
    4 Von Morgen
  3. Eleonore Laetitia Toufektchan
    7 Toufektchan
  4. Lisa Elfi Mohr
    4 Mohr
  5. Kevan Huai-Yee Chu
    5 Chu
  6. Aakanksha Rajiv Kapoor
    1 Kapoor
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