Special Issue "Chaperone-Mediated Autophagy"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Autophagy".

Deadline for manuscript submissions: closed (31 August 2019).

Special Issue Editors

Prof. Mario Tschan
Website
Guest Editor
Institute of Pathology, University of Bern, Bern, Switzerland
Interests: autophagy; CMA; acute myeloid leukemias; targeted cancer therapies; retinoids; transcription factors
Special Issues and Collections in MDPI journals
Dr. Magali Humbert
Website SciProfiles
Assistant Guest Editor
Institute of Pathology University of Bern, Bern 3008, Switzerland
Interests: autophagy; chaperone-mediated autophagy; acute myeloid leukemias; breast cancer; retinoids; differentiation therapy; transcription factors
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Chaperone-mediated autophagy (CMA) is a subtype of autophagy whereby the molecular chaperone HSC70/HSPA8 binds protein substrates containing a specific amino acid signature KFERQ (Lys-Phe-Glu-Arg-Gln) and targets them to the lysosome. The direct shuttling of soluble proteins trough the lysosomal membrane also requires the multimerization of LAMP2A, a lysosomal membrane-spanning protein, stabilized by HSP90. Physiological CMA, similar to macroautophagy, contributes to cellular homeostasis by protein quality control and the regulation of particular substrates involved in specific cellular pathways. More and more CMA substrates containing the KFERQ-like amino acid motif are being identified in parallel with the observation that a variety of diseases are affected by altered CMA activity. Of note, CMA may also be linked to cancerous glycolysis, as PKM2 and HK2, two key glycolytic enzymes highly expressed in cancer cells, are CMA substrates.

A better understanding of CMA regulation and function is the basis for proposing new treatment strategies in a variety of diseases and to develop new CMA targeting drugs. In neurodegenerative disease for instance, CMA deficiency—due to either substrate mutation or low LAMP2A expression—leads to an accumulation of protein aggregates that contributes to neuronal demise. In contrast, in a variety of cancers, CMA activity is increased, leading, for example, to the aberrant degradation of tumor suppressor proteins. Thus, on the one hand CMA supports the degradation of pathogenic proteins, on the other hand it promotes tumor cell proliferation. Extensive research remains to be done to understand the context-dependent impact of CMA on human health.

Moreover, CMA is involved in antigen presentation and T-cell signaling. CMA has been identified as a therapeutic target in autoimmune diseases. A first "CMA drug" in clinical trials to treat systemic lupus erythematosus (SLE) is the peptide P140/Lupuzor™, which attenuates CMA activity in lymphocytes.

This Special Issue of Cells is dedicated to all sorts of molecular, cellular and disease-associated aspects of CMA. In contrast to macroautophagy, there are currently fewer data on CMA regulation and function available. Therefore, we are really looking forward to receiving your manuscripts on this exciting topic to start closing this knowledge gap.

Thank you in advance for submitting your contributions for publication in this Special Issue of Cells.

Sincerely,

Prof. Mario Tschan
Dr. Magali Humbert
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Chaperone-mediated autophagy
  • disease
  • therapy
  • LAMP2A
  • degradation
  • lysosome
  • CMA
  • cancer

Published Papers (3 papers)

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Review

Open AccessReview
Chaperone-Mediated Autophagy in the Liver:
Good or Bad?
Cells 2019, 8(11), 1308; https://doi.org/10.3390/cells8111308 - 24 Oct 2019
Cited by 2
Abstract
Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the virus replication. Increased cellular autophagy may kill the infected cell and terminate the infection without proper regulation. The mechanism of [...] Read more.
Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the virus replication. Increased cellular autophagy may kill the infected cell and terminate the infection without proper regulation. The mechanism of autophagy regulation during liver disease progression in HCV infection is unclear. The autophagy research has gained a lot of attention recently since autophagy impairment is associated with the development of hepatocellular carcinoma (HCC). Macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) are three autophagy processes involved in the lysosomal degradation and extracellular release of cytosolic cargoes under excessive stress. Autophagy processes compensate for each other during extreme endoplasmic reticulum (ER) stress to promote host and microbe survival as well as HCC development in the highly stressed microenvironment of the cirrhotic liver. This review describes the molecular details of how excessive cellular stress generated during HCV infection activates CMA to improve cell survival. The pathological implications of stress-related CMA activation resulting in the loss of hepatic innate immunity and tumor suppressors, which are most often observed among cirrhotic patients with HCC, are discussed. The oncogenic cell programming through autophagy regulation initiated by a cytoplasmic virus may facilitate our understanding of HCC mechanisms related to non-viral etiologies and metabolic conditions such as uncontrolled type II diabetes. We propose that a better understanding of how excessive cellular stress leads to cancer through autophagy modulation may allow therapeutic development and early detection of HCC. Full article
(This article belongs to the Special Issue Chaperone-Mediated Autophagy)
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Open AccessReview
Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies
Cells 2019, 8(10), 1260; https://doi.org/10.3390/cells8101260 - 16 Oct 2019
Cited by 1
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Chaperone-Mediated Autophagy)
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Open AccessReview
HSPA8/HSC70 in Immune Disorders: A Molecular Rheostat that Adjusts Chaperone-Mediated Autophagy Substrates
Cells 2019, 8(8), 849; https://doi.org/10.3390/cells8080849 - 07 Aug 2019
Cited by 3
Abstract
HSPA8/HSC70 is a molecular chaperone involved in a wide variety of cellular processes. It plays a crucial role in protein quality control, ensuring the correct folding and re-folding of selected proteins, and controlling the elimination of abnormally-folded conformers and of proteins daily produced [...] Read more.
HSPA8/HSC70 is a molecular chaperone involved in a wide variety of cellular processes. It plays a crucial role in protein quality control, ensuring the correct folding and re-folding of selected proteins, and controlling the elimination of abnormally-folded conformers and of proteins daily produced in excess in our cells. HSPA8 is a crucial molecular regulator of chaperone-mediated autophagy, as a detector of substrates that will be processed by this specialized autophagy pathway. In this review, we shortly summarize its structure and overall functions, dissect its implication in immune disorders, and list the known pharmacological tools that modulate its functions. We also exemplify the interest of targeting HSPA8 to regulate pathological immune dysfunctions. Full article
(This article belongs to the Special Issue Chaperone-Mediated Autophagy)
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