QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online May 24, 2006
doi: 10.1242/10.1242/jcs.03019

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Appenzeller-Herzog, C. Articles by Hauri, H.-P. Search for Related Content PubMed PubMed Citation Articles by Appenzeller-Herzog, C. Articles by Hauri, H.-P.

The ER-Golgi intermediate compartment (ERGIC): in search of its identity and function

Christian Appenzeller-Herzog^* and Hans-Peter Hauri

Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland

View larger version (123K): [in a new window]   Fig. 1. Morphology of the ERGIC. (A) Ultrastructure of ERGIC clusters (circled). Immunogold-labeled ultrathin cryosection of a HepG2 cell showing the subcellular distribution of the ERGIC marker ERGIC-53 (10 nm gold) and the rough ER marker protein disulfide isomerase (5 nm gold). Modified and reprinted with permission from Klumperman et al. (Klumperman et al., 1998). (B) Close apposition of ERGIC clusters and ER-exit sites (ERES) visualized by confocal double immunofluorescence microscopy. HeLa cells were fixed, permeabilized and stained for the ERGIC marker ERGIC-53 and the ERES marker Sec31, a subunit of COPII (anti-Sec31 was kindly provided by Wanjin Hong, Institute of Molecular and Cell Biology, Singapore). Note that the majority of ERGIC-clusters are localized close to ERES. The enlargement of the boxed area (right-hand panel) shows partial overlap of ERGIC-53 and Sec31. Bar, 5 µm. (Micrograph kindly provided by Houchaima Ben-Tekaya, University of Basel, Basel, Switzerland.)

View larger version (40K): [in a new window]   Fig. 2. Models for ER-to-Golgi transport in mammalian cells. (A) The transport complex (TC) model. Upon budding from ER-exit sites (ERES), COPII vesicles tether and fuse to form pleiomorphic TCs, which in turn are transported along the microtubule cytoskeleton (MT) in a dynein-motor-dependent way. Relocation of a TC is accompanied by the progressive, COPI-mediated segregation of an anterograde cargo-rich domain (AD) from a retrograde cargo-rich domain (RD/COPI). At the cis-Golgi, incoming TCs gather and undergo fusion. Depending on the model for intra-Golgi transport (Rabouille and Klumperman, 2005), they either directly fuse with the first cisterna of the cis-Golgi or form a new cis-Golgi cisterna by homotypic fusion. (B) Stable compartment model of anterograde membrane traffic through the ERGIC. Short-range vesicular transport from ERES to the ERGIC depends on COPII but is microtubule independent. Conversely, long-range transport from ERGIC to cis-Golgi requires microtubules and the dynein motor. Fission of anterograde cargo-rich ACs from the ERGIC may involve the COPI coat, the spectrin/ankyrin skeleton, ZW10, as well as dynein and its membrane adaptor complex dynactin. Targeting of membrane carriers to the correct acceptor compartment is orchestrated by the tethering machinery. First, Rab1 is activated and thereby recruited to the membrane by guanine nucleotide exchange factors (GEFs), such as the TRAPP complex (zigzag-arrows, the GEF for Rab1 during ER exit is not known). Activated Rab1 recruits p115 to ERES (Allan et al., 2000), which is responsible for the subsequent docking of ER-derived vesicles to the ERGIC (Cao et al., 1998). For ERGIC-to-cis-Golgi transport there are two possible scenarios. In the first (green box), p115 binds to the ERGIC through activated Rab1, and docking at the cis-Golgi involves a p115-Rab1-GM130-GRASP65 tether (Moyer et al., 2001). In the second (yellow box), the GM130-GRASP65 complex recycles from the cis-Golgi to the ERGIC (Marra et al., 2001), and docking at the Golgi involves the Rab1-coordinated interaction of GM130-p115 with the transmembrane protein giantin (Beard et al., 2005; Sonnichsen et al., 1998). Membrane docking in all cases is followed by SNARE-mediated membrane fusion that requires catalysis by p115 (red star) (Sapperstein et al., 1996; Shorter et al., 2002). For simplicity Golgi-to-ER retrograde pathways are not shown.

View larger version (24K): [in a new window]   Fig. 3. pH-dependent sorting between the ER and ERGIC. Proteins travel between the ER and the ERGIC in anterograde and retrograde directions. The pH of the ER is 7.4 (Wu et al., 2001), whereas that of the ERGIC is more acidic. The scheme shows three different pH-dependent sorting mechanisms of anterograde-directed and/or recycling proteins in the early secretory pathway. ERGIC-53 functions as a transport receptor for the secretory/lysosomal protein procathepsin Z (pro-catZ). Association between ERGIC-53 and pro-catZ occurs in the ER at neutral pH, and dissociation occurs in the ERGIC following protonation of the ligand-binding site in ERGIC-53 (Appenzeller-Herzog et al., 2004). ERGIC-53 is then recycled back to the ER; pro-catZ proceeds through the secretory pathway. The LDL receptor-related protein (LRP) forms a complex with the escort protein RAP (Bu et al., 1995), which inhibits receptor-ligand interactions in the early secretory pathway. Again, low pH in the ERGIC triggers the dissociation of the two proteins. Subsequently, RAP is recycled back to the ER, probably by the KDEL receptor (KDEL-R), and LRP travels through the Golgi to the cell surface. By contrast, binding of the KDEL receptor to escaped ER proteins containing a C-terminal KDEL signal is thought to require the acidified pH in post-ER compartments (Scheel and Pelham, 1996). Ligand binding in turn triggers the retrograde transport of KDEL-receptor-ligand complexes from ERGIC and cis-Golgi to the ER.