ER-directed TREX1 limits cGAS activation at micronuclei.
APE1
BAF
STING
TREX1
cGAS
chromosome instability
chromothripsis
endoplasmic reticulum
micronuclei
nuclear envelope
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
18 02 2021
18 02 2021
Historique:
received:
12
05
2020
revised:
18
11
2020
accepted:
18
12
2020
pubmed:
22
1
2021
medline:
3
3
2021
entrez:
21
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33476576
pii: S1097-2765(20)30958-8
doi: 10.1016/j.molcel.2020.12.037
pmc: PMC7897315
mid: NIHMS1664453
pii:
doi:
Substances chimiques
Phosphoproteins
0
Nucleotidyltransferases
EC 2.7.7.-
cGAS protein, human
EC 2.7.7.-
Exodeoxyribonucleases
EC 3.1.-
three prime repair exonuclease 1
EC 3.1.16.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
724-738.e9Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA212290
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests J.M. has received consulting fees from Ono Pharmaceutical Co. His spouse is an employee of and has equity in Bristol Myers Squibb.
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