Substrate proteins are directly translocated into the lysosomal lumen through a dedicated multiprotein translocation complex. In this work, we have focused in a highly selective type of autophagy, known as chaperone-mediated autophagy (CMA), whereby individual proteins bearing a unique pentapeptide motif (KFERQ-like) are targeted for degradation in lysosomes upon binding to the heat shock cognate protein of 70 kDa (HSC70). Alterations in HSC proteostasis have been associated with a number of degenerative and malignant diseases, underscoring the importance of elucidating the precise contribution of components of the cellular proteostasis network to HSC maintenance. Maintenance of a fully functional proteome that can rapidly change to adjust to the status of HSC activation is facilitated in part by two major intracellular proteolytic pathways, the ubiquitin proteasome system and the autophagy/lysosomal system. Hematopoietic stem cells (HSC) harbor extensive self-renewal capabilities along with multilineage differentiation plasticity to sustain blood production over a lifetime.
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