Cytosolic ubiquitin protein degradation

Protein processing in the endoplasmic reticulum makes mistakes. All membrane-associated proteins and proteins that are secreted by the cell are synthesised on membrane-bound ribosomes and pass into the lumen of the reticulum, where they are modified by post-translational processes, so that much biochemical manipulation of the proteins takes place. Consequentially mistakes are often made. Such abnormal proteins are exported from the lumen into the cytosol for ubiquitination and degradation in the proteasome. 

Hill K, Cooper AA (2000) Degradation of unassembled Vphlp reveals novel aspects of the yeast ER quality control system. EMBO J 19 550-561 Hiller MM, Finger A, Schweiger M, Wolf D H (1996) ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science 273 1725-1728... 

Distinct from the lysosomal pathway are cytosolic mechanisms for degrading proteins. Chief among these mechanisms is a pathway that includes the chemical modification of a lysine side chain by the addition of ubiquitin, a 76-residue polypeptide, followed by degradation of the ubiquitin-tagged protein by a specialized proteolytic machine. Ubiquitination is a three-step process (Figure 3-13a) ... 

In unstimulated cells, NF-kB is localized to the cytosol, bound to an inhibitor protein, I-kB. In response to extracellular signals, phosphorylation-dependent ubiquitination and degradation of I-kB in proteasomes releases active NF-kB, which translocates to the nucleus (see Figure 14-28). 

Cellular proteins are degradated by two major routes, lysosomal and cytosolic ubiq-uitin (ATP-dependent) pathways. Other likely protein degradations include cytosolic Ca -dependent calpains (calpains I and II), cytosolic enzyme that is independent of both ATP and ubiquitin, mitochondria processing, endoplasmic reticulum and plasma membrane proteases (Bond and Butler, 1987). 

Proteasomes are the major cytosolic and nuclear protein degradation machineries and they are also responsible for the proteolysis of misfolded, ER-dislocated (endoplasmic reticulum) proteins [1-3]. Proteasomal protein turnover takes place in an ubiquitin-dependent manner. The proteasome-generated products - ohgopeptides varying in length from 3 to up to 30 amino acid residues - are further processed by aminopeptidases. In higher vertebrates, antigenic peptides are selected from the peptide pool produced by proteasomes and downstream aminopeptidases for presentation on the outer cell surface by major histocompatibility class 1 (MHCl) protein complexes. In this way, proteasomes are essential factors in the detection and eradication of virally infected cells. 

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