Intracellular LRG1 recruits MARCH2 to ubiquitinate and degrade endothelial VE-cadherin in septic lung injury.
Summary
This mechanistic study shows that endothelial intracellular LRG1 recruits MARCH2 to catalyze K48-linked polyubiquitination of VE-cadherin (Lys633), triggering proteasomal degradation and barrier failure in septic ALI. Genetic Lrg1 deletion or PROTAC-based pharmacology preserved VE-cadherin, reduced hyperpermeability, and mitigated lung injury in septic mice.
Key Findings
- Endothelial intracellular LRG1 is upregulated in septic ALI and promotes VE-cadherin degradation via MARCH2-mediated K48-linked polyubiquitination at Lys633.
- Loss of VE-cadherin disrupts adherens junctions, driving endothelial hyperpermeability and lung injury in septic mice.
- Genetic Lrg1 deletion or PROTAC-based intervention preserved VE-cadherin and mitigated endothelial leak and ALI.
Clinical Implications
Therapeutic strategies that block LRG1–MARCH2 interaction or prevent VE-cadherin ubiquitination may stabilize the endothelial barrier in sepsis-associated ALI/ARDS. This supports biomarker-driven patient stratification and informs development of PROTAC-guided approaches.
Why It Matters
It uncovers a previously unrecognized intracellular LRG1–MARCH2–VE-cadherin axis driving vascular leakage in sepsis, and demonstrates pharmacologic rescue, defining a tractable target for endothelial repair.
Limitations
- Preclinical models; absence of human tissue validation and clinical outcomes
- Potential off-target effects and translational safety of PROTAC strategy not characterized
Future Directions
Validate LRG1–MARCH2 signaling in human sepsis tissues; develop selective inhibitors or biologics targeting the axis; assess pharmacodynamics and safety in large animals before early-phase trials.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic experiments in cells and mouse models
- Study Design
- OTHER