Activation of innate immunity by mitochondrial dsRNA in mouse cells lacking p53 protein

Area of Science:

• Innate immunity
• Molecular biology
• RNA sensing

Background:

• Cytosolic innate immune sensors, such as RIG-I-like receptors, detect viral and cellular double-stranded RNA (dsRNA).
• Mitochondrial dsRNA, arising from mitochondrial DNA (mtDNA) transcription, is a source of endogenous dsRNA in the cytoplasm.

Purpose of the Study:

• To investigate the role of endogenous mitochondrial dsRNA in immune stimulation in Trp53 mutant mouse embryonic fibroblasts.
• To elucidate the mechanisms by which mitochondrial dsRNA activates innate immune responses.

Main Methods:

• Analysis of immune-stimulating dsRNA in Trp53 mutant mouse embryonic fibroblasts.
• Assessment of RIG-I-like receptor-mediated immune responses, including type I interferon and proinflammatory cytokine gene expression.
• Investigation of the role of RNase L in mitochondrial dsRNA processing and immune activation.
• Manipulation of mitochondrial transcription to evaluate its impact on dsRNA levels and immune responses.

Main Results:

• Trp53 mutant mouse embryonic fibroblasts harbor immune-stimulating endogenous dsRNA of mitochondrial origin.
• This mitochondrial dsRNA activates RIG-I-like receptors, leading to the induction of type I interferon and proinflammatory cytokines.
• RNase L cleaves mitochondrial dsRNA, enhancing RIG-I-like receptor activation.
• Interruption of mitochondrial transcription reduces the levels of immune-stimulatory dsRNA.

Conclusions:

• The tumor suppressor p53 plays a complex role in innate immunity beyond its known functions.
• Endogenous mitochondrial dsRNA is a significant trigger of innate immune responses, particularly in the context of p53 mutations.
• This finding sheds light on the involvement of endogenous RNA in diseases characterized by aberrant immune activation.