A group of cytosolic proteins are targeted to lysosomes for degradation in response to serum withdrawal or prolonged starvation by a process termed chaperone-mediated autophagy. In this proteolytic pathway little is known about how proteins are translocated across lysosomal membranes. We now show that an isoform of the constitutively expressed protein of the heat shock family of 70 kDa (Hsc70) is associated with the cytosolic side of the lysosomal membrane where it binds to substrates of this

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... oteolytic pathway. Results from coimmunoprecipitation and colocalization studies indicate that this molecular chaperone forms complexes with other molecular chaperones and cochaperones, including Hsp90, Hsp40, the Hsp70-Hsp90 organizing protein (Hop), the Hsp70-interacting protein (Hip), and the Bcl2-associated athanogene 1 protein (BAG-1). Antibodies against Hip, Hop, Hsp40 and Hsc70 block transport of protein substrates into purified lysosomes.