The reticulons: a family of proteins with diverse functions

Abstract

The reticulon family is a large and diverse group of membrane-associated proteins found throughout the eukaryotic kingdom. All of its members contain a carboxy-terminal reticulon homology domain that consists of two hydrophobic regions flanking a hydrophilic loop of 60-70 amino acids, but reticulon amino-terminal domains display little or no similarity to each other. Reticulons principally localize to the endoplasmic reticulum, and there is evidence that they influence endoplasmic reticulum-Golgi trafficking, vesicle formation and membrane morphogenesis. However, mammalian reticulons have also been found on the cell surface and mammalian reticulon 4 expressed on the surface of oligodendrocytes is an inhibitor of axon growth both in culture and in vivo. There is also growing evidence that reticulons may be important in neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. The diversity of structure, topology, localization and expression patterns of reticulons is reflected in their multiple, diverse functions in the cell.

Figure 1

Phylogenetic analysis of the reticulon homology domains (RHDs) of selected RTNs and RTNLPs. Alignments were created using the ClustalW2 program [99] and the tree was generated with Phylo_win software [100]. Bootstrap numbers are shown; the number of repetitions was 1,000. The tree was generated using the maximum likelihood method. GenBank accession numbers are as follows: H. sapiens RTN1A, NP_066959; H. sapiens RTN2A, NP_005610; H. sapiens RTN3A, NP_006045; H. sapiens RTN4A, NP_065393; M. musculus RTN1A, NP_703187; M. musculus RTN2B, NP_038676; M. musculus RTN3A, NP_001003934; M. musculus RTN4A, NP_918943; G. gallus RTN4, NP_989697; X. laevis RTN2A, NP_001089014; X. laevis RTN4, NP_001083238; D. rerio RTN4, NP_001018620; D. melanogaster Rtnl1A, NP_787987; C. elegans RET-1, NP_506656; S. cerevisiae RTNLA, NP_010077; A. thaliana RTNLB3, NP_176592.

Figure 2

The structure and membrane topology of reticulons. (a) Structure of reticulon proteins. Numbers refer to the exons that encode the protein regions. Black ovals represent hydrophobic regions. GenBank accession numbers are as in Figure 1. (b) Possible topologies of reticulon proteins in membranes. Although eight or more conformations are possible, only those for which evidence exists are depicted. Different topologies in different cell types and different membranes may enable reticulons to carry out diverse roles in the cell.

Figure 3

The expression and function of reticulons. (a) Myc-tagged reticulon constructs transfected into COS-7 cells show a reticular expression pattern. Scale bar, 70 μm. (b) Proteins known to interact with ER-associated and intracellular reticulons and their possible intracellular roles. Some classes of proteins may overlap in their cellular functions.

Figure 4

Interaction of Nogo-A with Nogo receptor. The interaction of Nogo-A (RTN4A) on oligodendrocytes and the Nogo receptor (NogoR) on neurons results in inhibition of axon regeneration after injury via Rho signaling [17,23,55,59,61-63,79]. The different regions of Nogo-A are colored as follows: red, 66-loop (Nogo66); green, Nogo-A-24; blue, Δ20. NogoR is in orange. The 66-loop interacts with NogoR to mediate growth-cone collapse and neurite outgrowth in vitro and to inhibit axon regeneration after injury [21,23,25,53,56,58,60,62]. The amino-terminal region Nogo-A-24 increases the binding affinity of Nogo-A to NogoR and also binds NogoR directly [15]. The amino-terminal region Δ20 can mediate fibroblast and growth-cone collapse independently of NogoR [16]. Some known co-receptors and signal transducers are listed beside the yellow symbol and are described in more detail in Table 1.