Angiogenesis is limited by LIC1-mediated lysosomal trafficking.

Area of Science:

• Cell Biology
• Molecular Biology
• Developmental Biology

Background:

• Dynein cytoplasmic 1 light intermediate chain 1 (LIC1) is crucial for the dynein motor complex, impacting endosomal recycling and lysosomal degradation.
• LIC1 interacts with Rab proteins and adaptor proteins like RILPL1/2, influencing cargo trafficking and cellular processes.
• Dysregulation of these pathways can affect cellular functions, including angiogenesis, the formation of new blood vessels.

Purpose of the Study:

• To investigate the role of LIC1 in regulating angiogenesis.
• To understand the molecular mechanisms by which LIC1 influences angiogenesis, particularly concerning VEGFR2 trafficking and signaling.
• To explore the involvement of Rab proteins and RILPL1/2 in LIC1-mediated angiogenesis regulation.

Main Methods:

• Generation and analysis of a dync1li1 zebrafish mutant with a premature stop codon.
• In vitro studies using LIC1-deficient human endothelial cells to assess VEGFR2 levels, SRC phosphorylation, and Rab11 activity.
• In vivo experiments involving endothelial-specific expression of active Rab11a and analysis of zebrafish mutants in rilpl1/2.

Main Results:

• The dync1li1 zebrafish mutant exhibited increased angiogenesis.
• LIC1-deficient human endothelial cells showed elevated cell surface VEGFR2, increased SRC phosphorylation, and enhanced Rab11-mediated recycling.
• Endothelial Rab11a activation and mutations in rilpl1/2 in zebrafish also led to excessive angiogenesis, mimicking LIC1 deficiency.

Conclusions:

• LIC1, along with RILPL1/2, restricts angiogenesis by promoting the degradation of VEGFR2-containing recycling endosomes.
• Disruption of LIC1 and RILPL1/2-mediated lysosomal targeting enhances Rab11-dependent recycling, leading to increased SRC signaling and angiogenesis.
• These findings highlight a novel role for LIC1 in controlling angiogenesis through the regulation of VEGFR2 trafficking and degradation.