A central role of the endoplasmic reticulum in the cell emerges from its functional contact sites with multiple organelles

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.

Keywords: Endosymbiosis; Lysosomes; Mitochondria; Organellar functions; Organelle disorders; Organelle interactions.

Fig. 1

Possible evolutionary scenario for the origin of eukaryotic cells and the role of the endomembrane system (ES)

Fig. 2

Scheme of the cell showing how the ER forms contacts with virtually all other intracellular membranous organelles

Fig. 3

ER–mitochondria contacts and cell physiology (see text for details)

Fig. 4

ERMITO and ER–endosome associations also involve a role in their fission. a Scheme of a mitochondrion with associated ER through interacting proteins VAPB (orange link) and PTPIP51 (green-link) proteins. b In yeast (top panel), ER–MITO contacts marked constriction and fission sites contain the ER–mitochondrial tethering complex (ERMES), mitochondrial nucleoid DNA, and the fission-machinery protein dynamin-related protein 1 (DNM1); c In mammalian cells (bottom panel), an ER-localized inverted formin (INF2), actin and myosin II are candidates for driving ER-associated constriction of mitochondria. Then, the fission-machinery protein dynamin-related protein 1 (DRP1) is recruited by adaptor proteins to ER-marked constrictions, where it drives fission. (Ab)| Live confocal fluorescence microscopy images of a Cos7 cell expressing mito-BFP (mitochondria in red) and mCherry–DRP1 (in cyan), merged with GFP–SEC61 β (ER in green) in the right panel. ER tubules contact two mitochondrial; c In ER-associated endosome fission in animal cells, cargo is sorted into tubules marked by the retromer, sorting nexins, and WASH complex protein FAM21. ER tubules are recruited to these sorting domains by an unidentified tether, and fission is rapid following ER recruitment. Note that another ER–endosome contact regulates dephosphorylation and internalization of epidermal growth factor receptor (EGFR) by ER-localized protein-Tyr phosphatase 1B (PTP1B)

Fig. 5

The STIM (ER)-Orai (PM) signaling and the formation of ER–PM contact sites