PACS2

PACS2 (Phosphofurin acidic cluster sorting protein 2) is a multifunctional sorting protein localized at mitochondria-associated endoplasmic reticulum membranes (MAMs) that plays a critical role in maintaining ER homeostasis and MAM structural integrity. In sepsis-induced myopathy (SIM), PACS2 levels are significantly depleted, leading to MAM disruption and the activation of excessive FAM134B-mediated ER-phagy (reticulophagy), which contributes to muscle wasting. Therapeutic intervention using adeno-associated virus (AAV)-mediated overexpression of PACS2 has demonstrated the ability to restore MAM integrity and activate the ERK–MAPK signaling axis. This activation prevents the nuclear translocation of Transcription Factor EB (TFEB), thereby downregulating FAM134B and ameliorating skeletal muscle atrophy and dysfunction in preclinical models.

Other names

Phosphofurin acidic cluster sorting protein 2