Urban planning of the endoplasmic reticulum (ER): how diverse mechanisms segregate the many functions of the ER

Abstract

The endoplasmic reticulum (ER) is the biggest organelle in most cell types, but its characterization as an organelle with a continuous membrane belies the fact that the ER is actually an assembly of several, distinct membrane domains that execute diverse functions. Almost 20 years ago, an essay by Sitia and Meldolesi first listed what was known at the time about domain formation within the ER. In the time that has passed since, additional ER domains have been discovered and characterized. These include the mitochondria-associated membrane (MAM), the ER quality control compartment (ERQC), where ER-associated degradation (ERAD) occurs, and the plasma membrane-associated membrane (PAM). Insight has been gained into the separation of nuclear envelope proteins from the remainder of the ER. Research has also shown that the biogenesis of peroxisomes and lipid droplets occurs on specialized membranes of the ER. Several studies have shown the existence of specific marker proteins found on all these domains and how they are targeted there. Moreover, a first set of cytosolic ER-associated sorting proteins, including phosphofurin acidic cluster sorting protein 2 (PACS-2) and Rab32 have been identified. Intra-ER targeting mechanisms appear to be superimposed onto ER retention mechanisms and rely on transmembrane and cytosolic sequences. The crucial roles of ER domain formation for cell physiology are highlighted with the specific targeting of the tumor metastasis regulator gp78 to ERAD-mediating membranes or of the promyelocytic leukemia protein to the MAM.

Fig. 1

ER subdomains, and selected markers. Rough Endoplasmic Reticulum (rER) sheets are characterized by ribosomes (pink ovals) which associate with translocon components (green rectangles) and ribophorins (purple ovals). Climp63 (yellow rectangle) is an important structural protein of the rER that also associates with microtubules. The ERQC (ER quality control compartment) is derived from the rER and also features translocon components (green rectangle) and associated proteins such as Derlin-1 (yellow square) and EDEM-1 (pink square) that facilitate the ubiquitination and retrotranslocation of misfolded proteins from the ER. Smooth Endoplasmic Reticulum (sER) tubule formation is in part mediated by the reticulons (purple circles) and atlastins (yellow circles). At the PAM (Plasma membrane-associated Membrane), STIM1 (purple rectangle) oligomerizes to form a pore which associates with the plasma membrane calcium channel ORAI1 (dark blue rectangle), mediating store operated calcium entry. The MAM (Mitochondria Associated Membrane) is a section of smooth ER that makes close contacts with mitochondria. ACAT1 (black squiggle) localizes to MAMs via a mitochondrial targeting sequence in its cytosolic tail, whereas other MAM proteins target to cholesterol-rich lipid domains within the MAM (pink membrane section). ER exit sites (ERES) at the transitional ER mark the point where COPII coated vesicles bud off from the ER en route to the ERGIC and Golgi compartments; ERES formation depends on Sec16 (small green circles), which associates with the ER membrane on the cytosolic face. Proteins destined for the peroxisomes sort into the pre-peroxisomal compartment, where they bud off into pre-peroxisomal vesicles in a Pex3 (small blue circle) -dependent manner. Lipid droplets are characterized by the presence of selected ER proteins including AAM-B. The nuclear envelope is equipped with ribosomes on the cytoplasmic face, where nesprins (pink ovals) are also found.