Phosphofurin acidic cluster sorting protein 2 (PACS2)

Phosphofurin acidic cluster sorting protein 2 (PACS2) is a multifunctional intracellular sorting adaptor protein that orchestrates the dynamic interactions between cellular membranes, most notably by tethering mitochondria to the endoplasmic reticulum (ER) to form mitochondria‐associated membranes (MAMs), which function as critical platforms for lipid synthesis, calcium signaling, and chaperone distribution. PACS2 directs the trafficking of membrane proteins by recognizing phosphorylated acidic cluster motifs and modulates protein localization within intracellular compartments, such as the ER and plasma membrane. The protein is pivotal in regulating cell fate by serving as a switch between autophagy and apoptosis—its depletion disrupts mitophagosome formation, impairing autophagy while potentiating apoptosis, as demonstrated in vascular smooth muscle cells under atherogenic stress. PACS2 is involved in apoptotic pathways, including translocation of proapoptotic effectors like Bid and Bax, and acts as a mediator in death receptor signaling (e.g., TRAIL‐induced apoptosis). Genetic disruption of PACS2 causes developmental and epileptic encephalopathies (DEE66/EIEE66), characterized by early-onset seizures, cerebellar abnormalities, and neurodevelopmental impairment. In addition, PACS2 is exploited by viral proteins, such as HIV-1 Nef, to facilitate immune evasion. PACS2’s diverse functions underscore its importance in cell homeostasis, apoptosis, organelle communication, and human disease.

Other names

KIAA0602PACS1LPACS-2DEE66EIEE66PACS1-like protein

Not applicable (no known drugs directly targeting PACS2)