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Regulated intramembrane proteolysis: emergent role in cell signalling pathways
Aonghus J McCarthy1, Caroline Coleman-Vaughan1, Justin V McCarthy2
1Signal Transduction Laboratory, School of Biochemistry and Cell Biology, Analytical and Biological Chemistry Research Facility (ABCRF), Western Gateway Building, University College Cork, Cork, Ireland.
Abstract:
Receptor signalling events including those initiated following activation of cytokine and growth factor receptors and the well-characterised death receptors (tumour necrosis factor receptor, type 1, FasR and TRAIL-R1/2) are initiated at the cell surface through the recruitment and formation of intracellular multiprotein signalling complexes that activate divergent signalling pathways. Over the past decade, research studies reveal that many of these receptor-initiated signalling events involve the sequential proteolysis of specific receptors by membrane-bound proteases and the γ-secretase protease complexes. Proteolysis enables the liberation of soluble receptor ectodomains and the generation of intracellular receptor cytoplasmic domain fragments. The combined and sequential enzymatic activity has been defined as regulated intramembrane proteolysis and is now a fundamental signal transduction process involved in the termination or propagation of receptor signalling events. In this review, we discuss emerging evidence for a role of the γ-secretase protease complexes and regulated intramembrane proteolysis in cell- and immune-signalling pathways.
Insights
Regulated intramembrane proteolysis, involving sequential receptor proteolysis by proteases like gamma-secretase, is a key cell signaling mechanism. This process influences both cell and immune signaling pathways.
Area of Science:
- Cellular Biology
- Molecular Biology
- Immunology
Background:
- Receptor signaling pathways are initiated at the cell surface via multiprotein complex formation.
- Cytokine, growth factor, and death receptors (e.g., TNF-R1, FasR, TRAIL-R1/2) activate diverse signaling cascades.
- Recent research highlights the role of sequential receptor proteolysis in these signaling events.
Purpose of the Study:
- To review the emerging evidence for the involvement of gamma-secretase protease complexes in cell and immune signaling.
- To discuss the mechanism and significance of regulated intramembrane proteolysis (RIP) in receptor-initiated signaling.
Main Methods:
- Literature review of studies on receptor signaling, proteolysis, and gamma-secretase.
- Analysis of the role of regulated intramembrane proteolysis in signal transduction.
- Synthesis of current understanding of RIP in cell and immune pathways.
Main Results:
- Many receptor-initiated signaling events involve sequential proteolysis of receptors by membrane-bound and gamma-secretase proteases.
- Proteolysis liberates soluble ectodomains and generates intracellular cytoplasmic fragments.
- Regulated intramembrane proteolysis is a fundamental process for signal transduction, affecting pathway termination or propagation.
Conclusions:
- Gamma-secretase protease complexes and regulated intramembrane proteolysis play a crucial role in cell- and immune-signaling pathways.
- RIP is a fundamental mechanism controlling the outcome of receptor-initiated signaling.
- Further research is needed to fully elucidate the scope and implications of RIP in biological systems.
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