Abstract
Chaperone-mediated autophagy (CMA) ensures the selective degradation of cellular proteins endowed with a KFERQ-like motif by lysosomes. It is estimated that 30% of all cellular proteins can be directed to the lysosome for CMA degradation, but only a few substrates have been formally identified so far. Mechanistically, the KFERQ-like motifs present in substrate proteins are recognized by the molecular chaperone Hsc70c (Heat shock cognate 71 kDa protein cytosolic), also known as HSPA8, and directed to LAMP2A, which acts as the CMA receptor at the lysosomal surface. Following linearization, the protein substrate is next transported to the lumen of the lysosomes, where it is degraded by resident proteases, mainly cathepsins and eventually recycled to sustain cellular homeostasis. CMA is induced by different stress conditions, including energy deprivation that also activates macro-autophagy (MA), that may make it difficult to decipher the relative impact of both pathways on cellular homeostasis. Besides common inducing triggers, CMA and MA might be induced as compensatory mechanisms when either mechanism is altered, as it is the often the case in different pathological settings. Therefore, CMA activation can compensate for alterations of MA and vice versa. In this context, these compensatory mechanisms, when occurring, may be targeted for therapeutic purposes. Both processes have received particular attention from scientists and clinicians, since modulation of MA and CMA may have a profound impact on cellular proteostasis, metabolism, death, differentiation, and survival and, as such, could be targeted for therapeutic intervention in degenerative and immune diseases, as well as in cancer, including hematopoietic malignancies. The role of MA in cancer initiation and progression is now well established, but whether and how CMA is involved in tumorigenesis has been only sparsely explored. In the present review, we encompass the description of the mechanisms involved in CMA, its function in the physiology and pathogenesis of hematopoietic cells, its emerging role in cancer initiation and development, and, finally, the potential therapeutic opportunity to target CMA or CMA-mediated compensatory mechanisms in hematological malignancies.
Highlights
Chaperone-mediated autophagy (CMA) represents one of the major pathways for protein degradation
The macromolecular complex constituted by Hsc70, its co-chaperones, and the protein substrate are routed to the lysosome, where the direct interaction between Hsc70 and the cytosolic domain of LAMP2A docks the complex to the lysosome
We reported recently that low LAMP2 expression levels that contribute to decreased CMA activity were associated with a poor overall survival in acute myeloid leukemia (AML) patients [47]
Summary
Called proteostasis, ensures the integrity of the proteome in multicellular organisms [1]. Proteostasis is closely connected to the signaling pathways involved in the detection of all forms of cellular stress that are capable of altering the proteome integrity [1]. This network comprises all the processes involved in RNA and protein synthesis and catabolism, including gene transcription, RNA translation and metabolism, protein synthesis, Cells 2019, 8, 1260; doi:10.3390/cells8101260 www.mdpi.com/journal/cells. Cells 2019, 8, 1260 and acquisition of the ternary structure of proteins, as well as all their post-translational regulations It includes the entire molecular web that regulates protein interactions, the mechanisms associated with the transport and localization of proteins in a defined subcellular compartment, and all the cellular processes implicated in protein catabolism. As the increasing role of macroautophagy (MA) in leukemogenesis has been recently treated [4], the present review will encompass the description of the mechanisms involved in CMA, the role of this highly specific degradative process in the physiology and pathogenesis of hematopoietic cells, its emerging function in cancer initiation and development, and, the potential therapeutic opportunity to target CMA or CMA-mediated compensatory mechanisms in cancer and, more specially, in hematopoietic malignancies
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