Selective Degradation of Cytosolic Proteins by Lysosomes

Lysosomes are able to internalize cellular proteins in a variety of ways. One pathway is selective for cytosolic proteins containing peptide sequences biochemically related to Lys-Phe-Glu-Arg-Gln (KFERQ). This pathway is activated in confluent monolayers of cultured cells in response to deprivation of serum growth factors and applies to approximately 30% of cytosolic proteins. We have reconstituted this lysosomal degradation pathway in vitro. Uptake and/or degradation is stimulated by ATP and a member of the heat shock 70-kilodalton protein family, the 73-kilodalton constitutive heat shock protein. Several possible mechanisms of selective protein transport into lysosomes and the possible relevance of this proteolytic pathway to the processing of the amyloid precursor protein are discussed.