Endoplasmic reticulum architecture: structures in flux

The endoplasmic reticulum (ER) is a dynamic pleiomorphic organelle containing continuous but distinct subdomains. The diversity of ER structures parallels its many functions, including secretory protein biogenesis, lipid synthesis, drug metabolism and Ca²⁺ signaling. Recent studies are revealing how elaborate ER structures arise in response to subtle changes in protein levels, dynamics, and interactions as well as in response to alterations in cytosolic ion concentrations. Subdomain formation appears to be governed by principles of self-organization. Once formed, ER subdomains remain malleable and can be rapidly transformed into alternative structures in response to altered conditions. The mechanisms that modulate ER structure are likely to be important for the generation of the characteristic shapes of other organelles.

Introduction

The many roles of the endoplasmic reticulum (ER) demand a high surface area and a distribution throughout the cytoplasm. The ER organizes the large amount of membrane required [1] by folding it into tubular or lamellar structures, generating a complex architecture that varies in response to functional requirements. Variations in ER organization are found not only in different cell types but also in different regions of the organelle within the same cell. Indeed, although the ER is a single, spatially continuous compartment [2, 3], it is composed of structurally and functionally different subdomains. Among these, the nuclear envelope and the peripheral ER are the most obvious [4, 5], but the ER contains other specialized subcompartments, such as the junctional regions between the ER and essentially every other organelle, and the exit sites where COPII-coated transport vesicles are generated [6]. As revealed by live cell imaging, many of these subdomains appear to be in a constant state of flux [3], suggesting that the ER has tremendous flexibility to alter structural organization, as necessary, to adapt to constantly changing cellular requirements. Indeed, physiological and developmental processes may rely on rapid ER restructuring, like that occurring in egg cells upon fertilization, in response to changes in cytosolic Ca²⁺ concentration [7].

Perhaps the first subdivision of the ER to be recognized was that between rough (ribosome-covered) and smooth (ribosome-free) domains (RER and SER) [8]. In many cells, RER and SER do not occupy spatially segregated regions, and small ribosome-free areas are interspersed with ribosome-covered regions. This type of ER is generally organized in sheets (cisternae) or in a branching tubular network typically seen in many cultured mammalian cells. Such networks are characterized by fairly straight tubules, which branch at tripartite junctions to generate a polygonal meshwork [5, 9]. Only in some cells (e.g. hepatocytes, steroid-synthesizing cells and neurons) do the smooth and rough portions of the ER occupy different regions of the cytoplasm. In these cases, the SER differs from the RER on the basis not only of its ribosome-free surface but also of its distinctive spatial organization.

In this review, we will discuss recent work on the factors that determine the formation of the ER branching tubular network, as well as on the mechanisms underlying the diverse architectural arrangements of the SER and its segregation from RER.