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Published on: May 2, 2018
A LY6E-PHB1-TRIM21 assembly degrades CD14 protein to mitigate LPS-induced inflammatory response
Xinyu Zhu1, Linxia Zhang1, Daobin Feng1
1Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences; Fudan University, Shanghai 201508, P. R. China.
Abstract:
A major theme of host against invading pathogens lies in multiple regulatory nodes that ensure sufficient signals for protection while avoiding excessive signals toward over-inflammation. The TLR4/MD-2/CD14 complex receptor-mediated response to bacterial lipopolysaccharide (LPS) represents a paradigm for understanding the proper control of anti-pathogen innate immunity. In this study, we studied the mechanism by which the glycosylphosphatidylinositol (GPI)-linked LY6E protein constrains LPS response via downregulating CD14. We first showed that LY6E downregulated CD14 via ubiquitin-dependent proteasomal degradation. The subsequent profiling of LY6E protein interactome led to the revelation that the degradation of CD14 by LY6E requires PHB1, which interacts with CD14 in a LY6E-dependent manner. Finally, we identified the PHB1-interacting TRIM21 as the major ubiquitin E3 ligase for the LY6E-mediated ubiquitination of CD14. Together, our study elucidated the molecular basis of LY6E-mediated governance of LPS response, alongside providing new insights to regulatory mechanisms controlling the homeostasis of membrane proteins.
Insights
The glycosylphosphatidylinositol (GPI)-linked LY6E protein limits lipopolysaccharide (LPS) response by degrading CD14. This involves PHB1 and the E3 ligase TRIM21, revealing a new regulatory mechanism for innate immunity.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Host defense against pathogens requires balancing protective immunity with preventing excessive inflammation.
- The Toll-like receptor 4 (TLR4)/MD-2/CD14 complex is crucial for responding to bacterial lipopolysaccharide (LPS).
- Dysregulation of LPS response can lead to detrimental inflammatory conditions.
Purpose of the Study:
- To elucidate the mechanism by which the GPI-linked protein LY6E regulates the host's response to LPS.
- To identify the molecular players involved in LY6E-mediated downregulation of CD14.
- To understand the regulation of membrane protein homeostasis in innate immunity.
Main Methods:
- Investigated LY6E's effect on CD14 levels and LPS response.
- Utilized ubiquitin-dependent proteasomal degradation assays.
- Performed protein interactome profiling to identify interacting partners.
- Identified ubiquitin E3 ligase activity using biochemical assays.
Main Results:
- LY6E downregulates CD14 through ubiquitin-dependent proteasomal degradation.
- PHB1 is essential for LY6E-mediated CD14 degradation, interacting with CD14 in a LY6E-dependent manner.
- TRIM21, interacting with PHB1, acts as the primary E3 ligase for CD14 ubiquitination by LY6E.
Conclusions:
- Elucidated the molecular mechanism of LY6E in governing LPS response via CD14 degradation.
- Identified a novel regulatory pathway involving LY6E, PHB1, and TRIM21 in controlling innate immunity.
- Provided new insights into the homeostasis of membrane proteins and inflammatory signaling.
