MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction

Area of Science:

• Cellular Biology
• Immunology
• Molecular Biology

Background:

• Necroptosis is a programmed cell death pathway involving mixed lineage kinase-like protein (MLKL).
• MLKL activation leads to plasma membrane rupture and release of damage-associated molecular patterns (DAMPs).
• The role of MLKL in mitochondrial DAMP release and subsequent immune activation is not fully understood.

Purpose of the Study:

• To investigate the role of MLKL in mitochondrial DNA (mtDNA) release.
• To determine if released mtDNA activates the cGAS-STING pathway.
• To evaluate the therapeutic potential of targeting the cGAS-STING pathway in necroptosis-mediated inflammation.

Main Methods:

• Utilized mouse models of necroptosis and inflammatory bowel disease (IBD).
• Investigated MLKL localization using cell biology techniques.
• Assessed mtDNA release and its impact on the cGAS-STING pathway.
• Interfered with the cGAS-STING pathway to evaluate therapeutic effects.

Main Results:

• Phosphorylated MLKL (phosphor-MLKL) translocates to mitochondria, inducing microtubule-dependent mtDNA release.
• Released mtDNA activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, upregulating interferon-beta (Ifnb).
• In an IBD mouse model, cGAS-STING pathway inhibition reduced inflammation and improved intestinal recovery.

Conclusions:

• MLKL induces inflammation through both cell-autonomous (mtDNA release) and cell non-autonomous (DAMP release) mechanisms.
• MLKL-mediated mtDNA release activates the cGAS-STING pathway, contributing to necroptosis-induced inflammation.
• Targeting the cGAS-STING pathway represents a potential therapeutic strategy for necroptosis-related inflammatory diseases like IBD.