Abstract
Early eukaryotic cells emerged from the compartmentalization of metabolic processes into specific organelles through the development of an endomembrane system (ES), a precursor of the endoplasmic reticulum (ER), which was essential for their survival. Recently, substantial evidence emerged on how organelles communicate among themselves and with the plasma membrane (PM) through contact sites (CSs). From these studies, the ER-the largest single structure in eukaryotic cells-emerges as a central player communicating with all organelles to coordinate cell functions and respond to external stimuli to maintain cellular homeostasis. Herein we review the functional insights into the ER-CSs with other organelles in a physiological perspective. We hypothesize that, in addition to the primitive role by the ES in the appearance of proto-eukaryotes, its successor-the ER-emerges as the key coordinator of inter-organelle/PM communication. The ER thus appears to be the 'maestro' driving eukaryotic cell evolution by incorporating new functions/organelles, while remaining the real coordinator overarching cellular functions and orchestrating them with the external milieu.