LYVAC/PDZD8 is a lysosomal vacuolator

Area of Science:

• Cell Biology
• Molecular Mechanisms
• Pathophysiology

Background:

• Lysosomal vacuolation is observed in various diseases, but its underlying molecular mechanisms are not well understood.
• The specific proteins and pathways involved in inducing lysosomal vacuolation require further elucidation.

Purpose of the Study:

• To identify the molecular mediators of lysosomal vacuolation.
• To elucidate the mechanism by which endoplasmic reticulum (ER)-anchored proteins contribute to lysosomal dysfunction.

Main Methods:

• Utilized human cell lines to investigate lysosomal vacuolation.
• Employed biochemical and imaging techniques to study protein recruitment and lipid transfer.
• Analyzed the role of PDZD8 in response to various vacuolation inducers.

Main Results:

• Identified PDZ domain-containing 8 (PDZD8), proposed to be renamed lysosomal vacuolator (LYVAC), as a general mediator of lysosomal vacuolation.
• Demonstrated that diverse inducers converge on lysosomal osmotic stress, recruiting LYVAC via multivalent interactions.
• Showcased LYVAC's lipid transfer domain sensing phosphatidylserine and cholesterol, mediating ER-to-lysosome lipid flux and lysosomal expansion.

Conclusions:

• LYVAC is a crucial ER-anchored protein mediating lysosomal vacuolation through lipid transfer and osmotic stress.
• The findings reveal a fundamental mechanism for lysosomal vacuolation with significant pathophysiological implications.