A LY6E-PHB1-TRIM21 assembly degrades CD14 protein to mitigate LPS-induced inflammatory response.

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.