Untangling the web: mechanisms underlying ER network formation

Abstract

The ER is a continuous membrane system consisting of the nuclear envelope, flat sheets often studded with ribosomes, and a polygonal network of highly-curved tubules extending throughout the cell. Although protein and lipid biosynthesis, protein modification, vesicular transport, Ca(2+)dynamics, and protein quality control have been investigated in great detail, mechanisms that generate the distinctive architecture of the ER have been uncovered only recently. Several protein families including the reticulons and REEPs/DP1/Yop1p harbor hydrophobic hairpin domains that shape high-curvature ER tubules and mediate intramembrane protein interactions. Members of the atlastin/RHD3/Sey1p family of dynamin-related GTPases interact with the ER-shaping proteins and mediate the formation of three-way junctions responsible for the polygonal structure of the tubular ER network, with Lunapark proteins acting antagonistically. Additional classes of tubular ER proteins including some REEPs and the M1 spastin ATPase interact with the microtubule cytoskeleton. Flat ER sheets possess a different complement of proteins such as p180, CLIMP-63 and kinectin implicated in shaping, cisternal stacking and cytoskeletal interactions. The ER is also in constant motion, and numerous signaling pathways as well as interactions among cytoskeletal elements, the plasma membrane, and organelles cooperate to position and shape the ER dynamically. Finally, many proteins involved in shaping the ER network are mutated in the most common forms of hereditary spastic paraplegia, indicating a particular importance for proper ER morphology and distribution in large, highly-polarized cells such as neurons. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.

Keywords: Atlastin; Endoplasmic reticulum; Hereditary spastic paraplegia; Morphology; REEP; Reticulon.

Fig 1

The ER network in cells. Schematic diagram showing the different structural features and morphologies of the continuous ER in animal cells.

Fig 2

Mechanisms involved in shaping the ER network. (A) Schematic diagram showing interconnected smooth ER tubules and peripheral sheets. (B) Sliding and TAC mechanisms involved in the formation and extension of ER tubules along stable, acetylated microtubule tracks and polymerizing microtubules, respectively. (C) ER shaping reticulons and atlastins on ER tubules, with a schematic depiction of atlastin-dependent tubule fusion. (D) ER proteins involved in formation and stabilization of ER sheets. Scaffolding proteins include p180 and kinectin. Adapted and modified from Lin et al. [8] and Pendin et al. [86].

Fig 3

Specialized nuclear envelope protein complexes. Top, Schematic diagram showing the continuous lumen between the nuclear membrane and the ER network. Bottom, Enlargements of the boxed areas in the top panel, showing the organization of the nuclear pore complex (left) and LINC complex (right). ER-shaping proteins are shown in green in the left panel. INM, inner nuclear membrane; ONM, outer nuclear membrane.