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Cited by 45

The DOI matches its Crossref record; 118 of the 118 references it cites were found in a registry or an index.

Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies

Robert, Guillaume, Jacquel, Arnaud, Auberger, Patrick·2019·Cells
DOI 10.3390/cells8101260PMC PMC6830112
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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.

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Figures

Figure 1 Schematic representation of the main processes of protein degradation. (1) MA (macro-autophagy) triggers the degradation of proteins, protein aggregates, lipids, and carbohydrates but also damaged organelles, as well as intracellular micro-organisms into the lysosomes. (2) Micro-autophagy corresponds to a less-selective form of autophagy that is carried out through the invagination of the lysosomal membrane around the material to be degraded. (3) Chaperone-mediated autophagy (CMA) allows the degradation of cytosolic proteins endowed with a KFERQ-like motif. During CMA, this motif is recognized by Hsc70, also called HSPA8, which triggers their unfolding and subsequent transport into the lysosome, where they are ultimately processed by lysosomal proteases. (4) Chaperone-assisted selective autophagy (CASA) ensures the selective ubiquitin-dependent degradation of dysfunctional chaperone-bound proteins in lysosomes. The ubiquitin proteasome system (UPS) is the cellular process by which short-lived proteins and dysfunctional or unfolded proteins are addressed to the proteasome for degradation.
Figure 1 Schematic representation of the main processes of protein degradation. (1) MA (macro-autophagy) triggers the degradation of proteins, protein aggregates, lipids, and carbohydrates but also damaged organelles, as well as intracellular micro-organisms into the lysosomes. (2) Micro-autophagy corresponds to a less-selective form of autophagy that is carried out through the invagination of the lysosomal membrane around the material to be degraded. (3) Chaperone-mediated autophagy (CMA) allows the degradation of cytosolic proteins endowed with a KFERQ-like motif. During CMA, this motif is recognized by Hsc70, also called HSPA8, which triggers their unfolding and subsequent transport into the lysosome, where they are ultimately processed by lysosomal proteases. (4) Chaperone-assisted selective autophagy (CASA) ensures the selective ubiquitin-dependent degradation of dysfunctional chaperone-bound proteins in lysosomes. The ubiquitin proteasome system (UPS) is the cellular process by which short-lived proteins and dysfunctional or unfolded proteins are addressed to the proteasome for degradation.CC BY · PubMed Central
Figure 2 The different steps of CMA. (1) Formation of protein complex (Hsc70 + co-chaperones). (2) Formation of the chaperone protein complex (Hsc70 complex + protein substrate). (3) Binding of the substrate–chaperone complex to LAMP2A. (4) Assembly of LAMP2A subunits to form a channel in the lysosomal membrane. (5) Linearization, internalization, and degradation of the protein substrate into the lysosome. (6) Dissociation of LAMP2A multimer. Abbreviations: CMA, chaperone-mediated autophagy; EF1-α, elongation factor 1 α; GFAP, glial fibrillary acidic protein; Hsc70, heat-shock cognate protein of 70 kDa; LAMP2A, lysosome-associated membrane protein type 2A; Lys-Hsc70, lysosome-associated hsc70.
Figure 2 The different steps of CMA. (1) Formation of protein complex (Hsc70 + co-chaperones). (2) Formation of the chaperone protein complex (Hsc70 complex + protein substrate). (3) Binding of the substrate–chaperone complex to LAMP2A. (4) Assembly of LAMP2A subunits to form a channel in the lysosomal membrane. (5) Linearization, internalization, and degradation of the protein substrate into the lysosome. (6) Dissociation of LAMP2A multimer. Abbreviations: CMA, chaperone-mediated autophagy; EF1-α, elongation factor 1 α; GFAP, glial fibrillary acidic protein; Hsc70, heat-shock cognate protein of 70 kDa; LAMP2A, lysosome-associated membrane protein type 2A; Lys-Hsc70, lysosome-associated hsc70.CC BY · PubMed Central

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Metadata

Authors
Robert, G., Jacquel, A., & Auberger, P.
Affiliations
Mediterranean Center for Molecular Medicine ,Université Nice Côte d’Azur, C3M/Inserm1065, 06100 Nice, France
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2019-10-16
Volume
8
Issue
10
Pages
1260
ISSN
2073-4409
DOI
10.3390/cells8101260
PMC
PMC6830112
Cited by
45
References
118
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Fondation ARC pour la Recherche sur le Cancer (Equipe labellisée 2017-19-PGA1 RF20170205389)
  • Institut National Du Cancer (PRTK 2017-2019)

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