Quality control in the endoplasmic reticulum: retrograde protein transport and its end in the proteasome

The endoplasmic reticulum (ER) is a membraneous organelle present in all eukaryotic cells, designed to deliver proteins to the plasma membrane, the lysosome (vacuole) or to the extracellular space. Such secretory proteins are synthezised in the cytoplasm and enter the ER in an unfolded form through a channel in the ER membrane. After entry into the ER proteins are folded, assembled and packed to be sent from there to their locus of action. Malfolded and therefore inactive molecules which otherwise would block the loci for active molecules have to be sorted out and destroyed. Thus the ER must contain a proofreading system which detects malfolded protein molecules, sorts them out and degrades them.

degradation of ER proteins

Up to then it was a biological dogma that proteins, that had entered the ER via the import channel were trapped in the organelle and destined for further secretion. It was therefore completely unexpected to discover, that after having detected that a protein is malfolded, this protein was retrograde transported from the ER back into the cytoplasm. Studies on a mutated carboxypeptidase yscY or a mutated ABC transporter Pdr5 showed that retrograde transport is followed by ubiquitination and degradation by the proteasome. These findings in yeast lead to an understanding of some diseases and processes that lead to disease. The hereditary disease cystic fibrosis is linked to degradation of a mutated cystic fibrosis transmembrane conductance regulator (CFTR) molecule which, like Pdr5, belongs to the ABC transporter family. Because of the mutation CFTR never reaches its locus of action, the plasma membrane, but is retained in the ER membrane instead where it is degraded via the ubiquitin-proteasome system. Viruses like cytomegalovirus or the human immunodeficiency virus type I (HIV type I) use the mechanism of retrograde protein transport from the ER to the cytoplasm and the proteasome to get rid of immunoprotective proteins of the host. Also toxins reach the cytoplasm of the host via the same retrograde transport system, where they develop their in part deadly effects. One can expect that studies on yeast will lead to further discovery of target molecules of this process which may be modulated by drugs to avoid development of disease.

Contact:

Prof. Dr. Dieter H. Wolf
Phone: +49-(711)-685-64390; Fax: -64392
e-mail: dieter.wolf[at]ibc.uni-stuttgart.de