Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies
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 fa...
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doaj-cba21319bf354afa8fada8bc6d1216192020-11-25T00:09:54ZengMDPI AGCells2073-44092019-10-01810126010.3390/cells8101260cells8101260Chaperone-Mediated Autophagy and Its Emerging Role in Hematological MalignanciesGuillaume Robert0Arnaud Jacquel1Patrick Auberger2Mediterranean Center for Molecular Medicine ,Université Nice Côte d’Azur, C3M/Inserm1065, 06100 Nice, FranceMediterranean Center for Molecular Medicine ,Université Nice Côte d’Azur, C3M/Inserm1065, 06100 Nice, FranceMediterranean Center for Molecular Medicine ,Université Nice Côte d’Azur, C3M/Inserm1065, 06100 Nice, FranceChaperone-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.https://www.mdpi.com/2073-4409/8/10/1260chaperone mediated autophagyhematological malignancieslysosomeprotein degradationcma targeting molecules |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Guillaume Robert Arnaud Jacquel Patrick Auberger |
spellingShingle |
Guillaume Robert Arnaud Jacquel Patrick Auberger Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies Cells chaperone mediated autophagy hematological malignancies lysosome protein degradation cma targeting molecules |
author_facet |
Guillaume Robert Arnaud Jacquel Patrick Auberger |
author_sort |
Guillaume Robert |
title |
Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies |
title_short |
Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies |
title_full |
Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies |
title_fullStr |
Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies |
title_full_unstemmed |
Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies |
title_sort |
chaperone-mediated autophagy and its emerging role in hematological malignancies |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2019-10-01 |
description |
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. |
topic |
chaperone mediated autophagy hematological malignancies lysosome protein degradation cma targeting molecules |
url |
https://www.mdpi.com/2073-4409/8/10/1260 |
work_keys_str_mv |
AT guillaumerobert chaperonemediatedautophagyanditsemergingroleinhematologicalmalignancies AT arnaudjacquel chaperonemediatedautophagyanditsemergingroleinhematologicalmalignancies AT patrickauberger chaperonemediatedautophagyanditsemergingroleinhematologicalmalignancies |
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