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Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies

Mediterranean Center for Molecular Medicine ,Université Nice Côte d’Azur, C3M/Inserm1065, 06100 Nice, France
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Cells 2019, 8(10), 1260; https://doi.org/10.3390/cells8101260
Received: 3 September 2019 / Revised: 4 October 2019 / Accepted: 11 October 2019 / Published: 16 October 2019
(This article belongs to the Special Issue Chaperone-Mediated Autophagy)
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. View Full-Text
Keywords: chaperone mediated autophagy; hematological malignancies; lysosome; protein degradation; CMA targeting molecules chaperone mediated autophagy; hematological malignancies; lysosome; protein degradation; CMA targeting molecules
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Robert, G.; Jacquel, A.; Auberger, P. Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies. Cells 2019, 8, 1260.

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