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Updated: Aug 7, 2025
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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
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Transposable elements activation triggers necroptosis in mouse embryonic stem cells
Lingmei Jin1,2,3, Jiangping He3,4, Huijian Feng2,3,5
1Institute of Digestive Disease, the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, B24 Yinquan South Road, Qingyuan, 511518, Guang Dong, China.
Cell Death & Disease
|March 7, 2023
Summary
SETDB1 deficiency triggers necroptosis in mouse stem cells by reactivating transposable elements (TEs). These TEs regulate RIPK3 expression and cause viral mimicry, activating the necroptosis pathway via ZBP1.
Area of Science:
- Epigenetics and Gene Regulation
- Cell Death Pathways
- Genomics and Retrovirology
Background:
- SETDB1 (histone H3K9 methyltransferase) deficiency in mouse embryonic stem cells (mESCs) induces RIPK3-dependent necroptosis.
- The precise mechanism of necroptosis pathway activation following SETDB1 loss remains unclear.
Purpose of the Study:
- To elucidate how the absence of SETDB1 activates the necroptosis pathway in mESCs.
- To investigate the role of transposable elements (TEs) in regulating RIPK3 and necroptosis.
Main Methods:
- Analysis of gene expression and epigenetic modifications (H3K9me3) in SETDB1-knockout mESCs.
- Investigating the regulatory roles of specific transposable elements (IAPLTR2_Mm, MMERVK10c-int) on RIPK3 expression.
- Assessing the impact of reactivated endogenous retroviruses and viral mimicry on necroptosis induction, particularly involving ZBP1.
Main Results:
- SETDB1 knockout leads to the reactivation of transposable elements (TEs), including IAPLTR2_Mm and MMERVK10c-int.
- These reactivated TEs function as enhancer-like elements, upregulating RIPK3 expression through cis-regulatory mechanisms.
- Reactivated endogenous retroviruses generate viral mimicry, activating necroptosis primarily through Z-DNA-binding protein 1 (ZBP1).
Conclusions:
- Reactivated transposable elements are key mediators of RIPK3 regulation and necroptosis induction upon SETDB1 deficiency.
- Both cis and trans regulatory mechanisms involving TEs contribute to the activation of the necroptosis pathway.
- TEs play a significant, previously underappreciated role in cellular death regulation.
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