Chaperone-mediated autophagy: roles in disease and aging

Cuervo, Ana María; Wong, Esther

doi:10.1038/cr.2013.153

Cited by 701 publications

(616 citation statements)

References 85 publications

Supporting

Mentioning

585

Contrasting

Unclassified

Order By: Relevance

“…Central to this quality is a balance between protein folding and protein degradation, the former controlled by cellular chaperones of the heat shock response, 1 and the latter by the ubiquitinproteasome system, 2 autophagy, 3 and other lysosome-dependent systems. 4 Recent data support the idea that these systems influence each other. 5,6 Existing in prokaryotes and eukaryotes, the heat shock protein chaperone system of protein folding and assembly as well as regulation of degradation of denatured proteins is more evolutionarily ancient 7 compared to autophagy, which is exclusively a eukaryotic process.…”

Section: Introductionmentioning

confidence: 80%

Heat shock response and autophagy—cooperation and control

2015

View full text Add to dashboard Cite

Abbreviations: AKT, v-akt murine thymoma viral oncogene homolog 1; AMPK, adenosine monophosphate-activated protein kinase; ATG, autophagy-related; BECN1, Beclin 1, autophagy related; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; HSF1, heat shock transcription factor 1; HSP, heat shock protein; HSPA8/ HSC70, heat shock 70kDa protein 8; IL, interleukin; LC3, MAP1LC3, microtubule-associated protein 1 light chain 3; MTMR14/ hJumpy, myotubularin related protein 14; MTOR, mechanistic target of rapamycin; NR1D1/Rev-Erb-a, nuclear receptor subfamily 1, group D, member 1; PBMC, peripheral blood mononuclear cell; PPARGC1A/PGC-1a, peroxisome proliferator-activated receptor, gamma, coactivator 1 a; RHEB, Ras homolog enriched in brain; SOD, superoxide dismutase; SQSTM1/p62, sequestosome 1; TPR, translocated promoter region, nuclear basket protein; TSC, tuberous sclerosis complex; ULK1, unc-51 like autophagy activating kinase 1.Protein quality control (proteostasis) depends on constant protein degradation and resynthesis, and is essential for proper homeostasis in systems from single cells to whole organisms. Cells possess several mechanisms and processes to maintain proteostasis. At one end of the spectrum, the heat shock proteins modulate protein folding and repair. At the other end, the proteasome and autophagy as well as other lysosome-dependent systems, function in the degradation of dysfunctional proteins. In this review, we examine how these systems interact to maintain proteostasis. Both the direct cellular data on heat shock control over autophagy and the time course of exercise-associated changes in humans support the model that heat shock response and autophagy are tightly linked. Studying the links between exercise stress and molecular control of proteostasis provides evidence that the heat shock response and autophagy coordinate and undergo sequential activation and downregulation, and that this is essential for proper proteostasis in eukaryotic systems.

show abstract

Section: Introductionmentioning

confidence: 80%

Heat shock response and autophagy—cooperation and control

2015

View full text Add to dashboard Cite

show abstract

“…Chaperone-mediated autophagy is distinct from macro autophagy and microautophagy because cargo is not sequestered within a membrane delimited vesicle. Instead, proteins targeted by chaperonemediate d autophagy contain a KFERQ-like pentapetide motif that is recognized by the cytosolic chaperone heat shock cognate 70 kDa protein (HSC70); HSC70 promotes the translocation of these targets across lysosomal membranes into the lysosomal lumen via the lysosomalassociated membrane protein 2A (LAMP2A) receptor 8 . This Review focuses on macroautophagy, which we hereafter call autophagy.…”

Section: Overview Of the Autophagic Pathwaymentioning

confidence: 99%

Autophagy at the crossroads of catabolism and anabolism

Kaur

Debnath

2015

Nat Rev Mol Cell Biol

826

801

View full text Add to dashboard Cite

“…CMA is a complex process that can be divided into four distinct steps: (1) binding of substrates to the chaperone protein Hsc70 and targeting to lysosomes; (2) binding of substrates to the lysosomal receptor LAMP2A (lysosomeassociated membrane protein type 2A) and unfolding; (3) substrate translocation into lysosomes; and (4) substrate degradation by hydrolytic enzymes in the lysosomal lumen [21] .…”

Section: Molecular Mechanisms Of Cmamentioning

confidence: 99%

“…and Hsc70, are robustly expressed in the CNS [51,52] ; CMA is involved in the regulation of neuronal survival [30] ; and CMA dysfunction has been linked to the pathogenic processes of several human disorders [21] .…”

Section: Cma and Neuroprotectionmentioning

confidence: 99%

Chaperone-mediated autophagy: roles in neuroprotection

et al. 2015

View full text Add to dashboard Cite

Chaperone-mediated autophagy (CMA), one of the main pathways of lysosomal proteolysis, is characterized by the selective targeting and direct translocation into the lysosomal lumen of substrate proteins containing a targeting motif biochemically related to the pentapeptide KFERQ. Along with the other two lysosomal pathways, macro-and micro-autophagy, CMA is essential for maintaining cellular homeostasis and survival by selectively degrading misfolded, oxidized, or damaged cytosolic proteins. CMA plays an important role in pathologies such as cancer, kidney disorders, and neurodegenerative diseases. Neurons are post-mitotic and highly susceptible to dysfunction of cellular quality-control systems. Maintaining a balance between protein synthesis and degradation is critical for neuronal functions and homeostasis. Recent studies have revealed several new mechanisms by which CMA protects neurons through regulating factors critical for their viability and homeostasis. In the current review, we summarize recent advances in the understanding of the regulation and physiology of CMA with a specifi c focus on its possible roles in neuroprotection.Keywords: chaperone-mediated autophagy; cellular homeostasis; neuroprotection; neuronal death; neurodegenerative disease ·Review· IntroductionMaintaining the balance between protein synthesis and degradation contributes to cellular homeostasis [1][2][3] . The ubiquitin-proteasome system (UPS) and the autophagylysosome pathway (ALP) are major systems present in almost all cell types to mediate the degradation of intracellular proteins into their constitutive amino-acids [4,5] .The UPS is a multi-subunit protease complex that degrades proteins tagged with one or more covalently-bound ubiquitin molecules, and most proteasome substrates are proteins with a short half-life [6,7] .In contrast to the UPS, the ALP is mainly responsible for the degradation of long-lived proteins and organelles.On the basis of the mechanism used for delivery of intracellular cargoes to lysosomes, autophagy can be divided into three types: macroautophagy (MA), microautophagy, and chaperone-mediated autophagy (CMA) [8,9] . Both CMA and MA have been identified in mammals as processes important for damage and diseases of the central nervous system [10] . MA is a bulk degradation system that involves the formation of a double-membrane structure (autophagosome) that sequesters damaged organelles and proteins. The autophagosome acquires the hydrolytic enzymes necessary to degrade its cargo by fusing with lysosomes [11] . Microautophagy traps nonspecifi c cytoplasm inside vesicles via direct invagination of the lysosomal membrane. These vesicles "pinch off" into the lumen and are degraded by lysosomal hydrolases [12] .CMA is the third type of autophagy, and has so far been found only in mammalian cells [13,14] . One of its intrinsic features is the selective targeting and direct translocation into the lysosomal lumen of substrate proteins containing a targeting motif related to the pentapeptide KFERQ [15,16] [17][1...

show abstract

Chaperone-mediated autophagy: roles in disease and aging

Cited by 701 publications

References 85 publications

Heat shock response and autophagy—cooperation and control

Heat shock response and autophagy—cooperation and control

Autophagy at the crossroads of catabolism and anabolism

Chaperone-mediated autophagy: roles in neuroprotection

Contact Info

Product

Resources

About