Translocation, retrograde

Xiong X, Chong E, Skach W R (1999) Evidence that endoplasmic reticulum (ER)-assodated degradation of cystic fibrosis transmembrane conductance regulator is linked to retrograde translocation from the ER membrane. J Biol Chem 274 2616-2624... 

The involvement of the proteasome suggests that the MHC class I heavy chains migrate back to the cytosol. Indeed, a cytosolic disposition of the deglycosylated intermediate can be confirmed by subcellular fractionation experiments. Furthermore, this intermediate can be immunoprecipitated from material reactive with anti-proteasome antibodies. Apparently, US2 and USll induce retrograde translocation, or dislocation , of MHC class I heavy chains from the ER to the cytosol, where the heavy chains are subjected to proteolytic degradation by the proteasome (Wiertz et al. 1996a,b). 

From these examples, it is evident that protein dislocation is a common pathway used by cells to dispose of misfolded proteins. It is obvious that proteins that are located in the ER lumen have to travel across the ER membrane before they can be degraded by the cytosolic proteasome. The question arises whether retrograde translocation is mediated by the translocon or by a completely different translocation system dedicated to dislocating proteins (reviewed in Kopito 1997). 

Microtubules are polymers of the protein tubulin which, in vivo, are probably always associated with other proteins, the Microtubule Associated Proteins (MAPs). Microtubules are the main structural components of mitotic and meiotic spindles, and of cilia and flagella in axons and dendrites, they serve as cables along which organelles are moved by kinesin and the retrograde translocator [R.D.Vale et al. Cell 43 (1986) 623-632]. Depending on the function of the microtubules, they are associated with different... 

MAPs may be defoed as proteins with specific binding sites for tubulins. It is not known whether dynein, kinesin and the retrograde translocator (see IG-nesin) are MAPs by this definition, because their affinity to microtubules may be mediated by other MAPs. The classic MAPs are listed below. 

Protein toxins acting intracellularly are often composed of two subunits (A/B model). One subunit is catalytic (A-subunit) and the other is responsible for binding and cell entry (B-subunit). Following binding to an extracellular membrane receptor, the toxins are endocytosed. From the endosomes, the A-subunit is directly (pH dqDendent) transferred into the cytosol (e.g., diphtheria toxin and anthrax toxin) or the toxin is transported in a retrograde manner via the golgi to the ER (e.g., cholera toxin), where translocation into the cytosol occurs [1]. 

The receptor for NGF is TrkA, a 140 kDa cell surface protein that specifically binds NGF, but not other neurotrophins [5, 6, 9]. TrkA is expressed on the neuronal cell body and on neuronal processes. In its action as a target-derived trophic factor, NGF is secreted within the target organ and it then binds to TrkA receptors present on the growing neuronal process or synapse. The NGF-TrkA complex is then internalized and subsequently translocated to the cell body by retrograde axonal transport. In those cells that respond to NGF through autocrine or paracrine mechanisms, the growth factor can bind to any of the widely distributed TrkA molecules on the neuronal membrane. 

Hashimoto R, Tanaka O, Otani H. Selective translocation of different makers in the ante- and retrograde pathways between the Golgi apparatus and the rough endoplasmic reticulum in a hybridoma cell line. Ann Anat 1997 179 105-116. 

Figure 1 The mode of action for bacterial AB-type exotoxins. AB-toxins are enzymes that modify specific substrate molecules in the cytosol of eukaryotic cells. Besides the enzyme domain (A-domain), AB-toxins have a binding/translocation domain (B-domain) that specifically interacts with a cell-surface receptor and facilitates internalization of the toxin into cellular transport vesicles, such as endosomes. In many cases, the B-domain mediates translocation of the A-domain into the cytosol by pore formation in cellular membranes. By following receptor-mediated endocytosis, AB-type toxins exploit normal vesicle traffic pathways into cells. One type of toxin escapes from early acidified endosomes (EE) into the cytosol, thus they are referred to as short-trip-toxins . In contrast, the long-trip-toxins take a retrograde route from early endosomes (EE) through late endosomes (LE), trans-Golgi network (TGN), and Golgi apparatus into the endoplasmic reticulum (ER) from where the A-domains translocate into the cytosol to modify specific substrates.

Plemper RK, and Wolf DH (1999) Retrograde protein translocation ERADication of secretory proteins in health and disease. Trends Biochem. Sci. 24 266-270. 

A. Rapak, P. O. Falnes, and S. Olsnes, Retrograde transport of mutant ricin to the endoplasmic reticulum with subsequent translocation to the cytosol, Proc. Natl. Acad. Sci. USA 94 3783-3788 (1997). 

Sorting to the final destination TeTx is translocated predominantly by retrograde axonal transport to the axodendritic area of the motoneurons in the spinal cord. Here, the toxin is released, probably by a transcytotic mechanism, crosses the synaptic cleft. 

Hendry, I.A., Johanson, S.O. and Heydon, K., (1995a) Nuclear translocation of the alpha subunit of the GTP-binding protein in dorsal root ganglia after retrograde axonal transport. Proc. Aust. Neurosci. Soc. 6 103. 

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