PACS-2 integrates interorganellar communication pathways of cellular homeostasis and apoptosis

Eukaryotic cells rely on a coordinated endomembrane system to maintain homeostasis, yet this same network also initiates apoptosis when cells are damaged or no longer needed. This work identifies the sorting protein PACS‑2 as a key regulator linking these processes. PACS‑2 directs trafficking within the endomembrane system, coordinates communication between the endoplasmic reticulum and mitochondria, and regulates calcium signaling and apoptotic activation. In response to apoptotic stimuli, PACS‑2 translocates Bid to mitochondria to promote caspase activation. Its phosphorylation state at Ser437 functions as a molecular switch, determining whether PACS‑2 supports cellular homeostasis or drives apoptosis.