Chaperone-mediated autophagy: a unique way to enter the lysosome world

Kaushik, Susmita; Cuervo, Ana María

doi:10.1016/j.tcb.2012.05.006

Cited by 714 publications

(647 citation statements)

References 79 publications

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“…Targeting of proteins for degradation by CMA and e‐MI requires a pentapeptide motif recognized by the hsc70 chaperone (Sahu et al ., 2011; Kaushik & Cuervo, 2012). Tau bears two of such motifs in its C‐terminal region which are required for its CMA targeting (Wang et al ., 2009).…”

Section: Discussionmentioning

confidence: 99%

Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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SummaryLoss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule‐stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients’ brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone‐mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age‐related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk‐associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

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Section: Discussionmentioning

confidence: 99%

Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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“…Proteins can be targeted from the cytosol to the lysosomal membrane and then gain access to the lumen of this organelle by directly crossing its membrane. This process is known as chaperone-mediated autophagy (CMA) and constitutes the focus of this review [4].…”

Section: Introductionmentioning

confidence: 99%

“…This allows for the removal of specific proteins without disturbance of neighboring ones and makes CMA an efficient system for degradation of damaged or abnormal proteins, and surplus subunits of multi-protein complexes. In addition, this selectivity permits CMA to play a regulatory role in multiple cellular processes by contributing to modulate intracellular levels of enzymes, transcription factors and cell maintenance proteins [4].…”

Section: Introductionmentioning

confidence: 99%

Chaperone-mediated autophagy: roles in disease and aging

2013

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This review focuses on chaperone-mediated autophagy (CMA), one of the proteolytic systems that contributes to degradation of intracellular proteins in lysosomes. CMA substrate proteins are selectively targeted to lysosomes and translocated into the lysosomal lumen through the coordinated action of chaperones located at both sides of the membrane and a dedicated protein translocation complex. The selectivity of CMA permits timed degradation of specific proteins with regulatory purposes supporting a modulatory role for CMA in enzymatic metabolic processes and subsets of the cellular transcriptional program. In addition, CMA contributes to cellular quality control through the removal of damaged or malfunctioning proteins. Here, we describe recent advances in the understanding of the molecular dynamics, regulation and physiology of CMA, and discuss the evidence in support of the contribution of CMA dysfunction to severe human disorders such as neurodegeneration and cancer.

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“…This selectivity allows for the removal of misfolded, oxidized, or damaged cytosolic proteins under physiological or Zhibiao Cai, et al Roles of CMA in neuroprotection 453 pathological conditions without perturbing normallyfunctioning forms of the same proteins [17][18][19] . CMA potentially regulates multiple cellular processes by the selective removal of inhibitors of transcription, enzymes, and cellmaintenance proteins [17,20] .…”

Section: Introductionmentioning

confidence: 99%

“…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][18][19] . CMA potentially regulates multiple cellular processes by the selective removal of inhibitors of transcription, enzymes, and cellmaintenance proteins [17,20] .In this review, we first briefly summarize the main mechanisms of CMA under physiological conditions and then discuss its roles in neuroprotection and the therapeutic potential of targeting this pathway for the treatment of brain diseases. …”

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confidence: 99%

Chaperone-mediated autophagy: roles in neuroprotection

et al. 2015

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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...

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Chaperone-mediated autophagy: a unique way to enter the lysosome world

Cited by 714 publications

References 79 publications

Interplay of pathogenic forms of human tau with different autophagic pathways

Interplay of pathogenic forms of human tau with different autophagic pathways

Chaperone-mediated autophagy: roles in disease and aging

Chaperone-mediated autophagy: roles in neuroprotection

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