Raver1 links Ripk1 RNA splicing to caspase-8-mediated pyroptotic cell death, inflammation, and pathogen resistance

Area of Science:

• Immunology
• Molecular Biology
• Cell Death Pathways

Background:

• Receptor-interacting serine/threonine kinase 1 (RIPK1) and caspase-8 are critical regulators of cell death and inflammation.
• Dysregulation of RIPK1 and caspase-8 contributes to various inflammatory diseases.

Purpose of the Study:

• To investigate the role of Raver1 in regulating RIPK1 splicing and its impact on inflammatory cell death.
• To elucidate the function of Raver1 in innate immune responses.

Main Methods:

• Analysis of Ripk1 pre-mRNA splicing in Raver1-deficient macrophages.
• Assessment of cell death, cytokine production (IL-18, IL-1ß), and immune signaling pathway activation (caspase-8, Gasdermin D/E, caspase-1) in response to various stimuli.
• Evaluation of Yersinia infection susceptibility in Raver1-deficient mice.

Main Results:

• Raver1 deficiency alters Ripk1 pre-mRNA splicing, leading to diminished inflammatory cell death and reduced cytokine production in macrophages.
• Raver1-deficient macrophages exhibit decreased activation of caspase-8, Gasdermin D/E, and caspase-1.
• Raver1-deficient mice display increased susceptibility to Yersinia infection.
• Raver1 and RIPK1 influence the expression and function of the C-type lectin receptor Mincle.

Conclusions:

• Raver1 is a crucial regulator of Ripk1 splicing and plays a pivotal role in controlling caspase-8-dependent inflammatory cell death.
• Raver1 modulates innate immune responses and is significant in directing inflammatory processes both in vitro and in vivo.
• Targeting Raver1 may offer therapeutic strategies for inflammatory conditions and infections.