Lysosomal protein degradation pathway

The problem we have not yet touched upon is how components can specifically move from one cellular component to another. Both the entry and the exit of SFV spike proteins are dependent on a number of such cellular processes. The newly synthesized spike proteins move from the ER to the Golgi complex and then to the cell surface. The cell surface membrane is continuously retrieved by endocytosis into endosomes. From here the endocytosed membrane components probably recycle back to the cell surface, but some components may also be channeled into lysosomes for degradation. Especially in cells with secretory activity, the recycling pathway from the cell surface also includes the Golgi complex (see Farquhar and Palade, 1981). 

Fig. 5.4 Endocytosis of GPCRs mediated by GRKs, arrestins and clathrin-coated pits. Receptor phosphorylation mediates recruitment of arrestins from the cytoplasm, the arres-tin interaction with other adaptotor proteins, and promotes receptor endocytosis by clathrin-coated pits. Internalised receptors may be sorted into a rapid recycling pathway, or to a degradative pathway into the lysosomes...

Fig. 6.2. Model for how FcRn rescues IgG from catabolism by recycling and transcytosis. IgG and many other soluble proteins are present in extracellular fluids. Vascular endothelial cells are active in fluid phase endocytosis of blood proteins. Material taken up by these cells enters the endosomes where FcRn is found as an integral membrane protein. The IgG then binds FcRn in this acidic environment. This binding results in transport of the IgG to the apical plasma membrane for recycling into the circulation, or to the basolateral membrane for transcytosis into the extracellular space. Exposure to a neutral pFI in both locations then results in the release of IgG. The remaining soluble proteins are channeled to the lysosomal degradation pathway.

Seglen PO, Gordon PB, Poli A. Amino acid inhibition of autophagic/lysosomal pathway of protein degradation in isolated rat hepatocytes. Biochim Biophys Acta 1980 630 103-118. 

Primarily, internalization is a means of removing excess, extracellular hormones by an active degradative pathway in lysosomes, thus terminating the hormone signal. Some other mechanisms of clearance of protein hormones are the following. 

Perez-Sala, D., Boya, P., Ramos, 1., Herrera, M., and Stamatakis, K. (2009). The C-terminal sequence of RhoB directs protein degradation through an endo-lysosomal pathway. PLoS One 4 e8117. 

If protein degradation is so quick, clearly it is a process that must be heavily controlled to avoid destruction of the wrong polypeptides. The degradation pathways are restricted to degradative subcellular organelles, such as lysosomes, or to macromolecular structures called proteasomes. Proteius are directed to lysosomes by specific signal sequences, often added in a posttranslational modification step. Once in the lysosome, the destruction is nonspecific. 

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). 

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