Cell surface protein aggregation triggers endocytosis to maintain plasma membrane proteostasis

Area of Science:

• Cellular Biology
• Proteostasis
• Endocytosis

Background:

• Intracellular proteostasis mechanisms are well-understood.
• Extracellular protein denaturation responses remain largely unknown.
• Cellular homeostasis depends on managing external proteotoxicity.

Purpose of the Study:

• To elucidate mechanisms for clearing extracellular protein aggregates.
• To identify novel endocytic pathways involved in proteostasis.
• To explore implications for pathological protein clearance and therapies.

Main Methods:

• Utilized ERBB2/HER2-specific antibodies to study receptor endocytosis.
• Investigated protein aggregation as a trigger for endocytosis.
• Characterized the aggregation-dependent endocytosis (ADE) pathway.
• Examined the role of actin, clathrin, and dynamin in ADE.

Main Results:

• Protein ectodomain aggregation triggers macroendocytosis and lysosomal degradation.
• ERBB2/HER2 receptor aggregation induces rapid, clathrin/dynamin-independent endocytosis.
• Canonical endocytic cargoes are redirected to the ADE pathway upon protein aggregation.
• ADE is an actin-driven process resembling macropinocytosis.
• Physical and chemical stress-induced protein aggregation also activates ADE.

Conclusions:

• Protein aggregation of extracellular domains is a trigger for rapid cellular uptake and lysosomal clearance.
• Aggregation-Dependent Endocytosis (ADE) is a novel pathway for managing extracellular proteotoxicity.
• ADE has potential implications for clearing pathological protein aggregates and enhancing antibody-based therapies.