ReviewChaperone-mediated autophagy: Molecular mechanisms and physiological relevance
Section snippets
Introduction: intracellular protein degradation and the lysosomal system
Maintaining a balance between protein synthesis and degradation is absolutely essential for proper cellular functioning, cellular homeostasis, and cell survival in a changing extracellular environment [1], [2]. Protein degradation thus wears several hats in cells: First, as a recycling system, it mediates the breakdown of proteins that are no longer needed into constitutive amino acid components, which can then be used in the synthesis of new proteins [1]. Second, protein degradation serves
Chaperone-mediated autophagy: general properties
CMA is a uniquely selective form of autophagy by which specific cytosolic proteins are transported one-by-one across the lysosomal membrane for degradation [10], [11]. Unlike the other forms of autophagy, in which portions of the cytoplasm are typically engulfed in bulk (although there are specific types of micro- and macroautophagy), CMA is extremely selective for a subset of cytosolic soluble proteins, whereas this pathway cannot degrade organelles. CMA is constitutively active in many cell
Molecular dissection of CMA
The distinctive characteristic of CMA – the selectivity for the degradation of a subset of soluble cytosolic proteins – is directly determined by two factors: the presence of a recognition-targeting motif in the amino acid sequence of the substrate proteins, and the fact that proteins access the lysosomal lumen one-by-one after unfolding [10]. The cytosolic and lysosomal molecular machineries that mediate this process are organized on the basis of these important features. They include the
Regulation of CMA
The signaling mechanisms involved in the activation of CMA and in the modulation of the activity of this autophagic pathway remain, for the most part, poorly characterized. In contrast, the local regulation of CMA at the lysosomal compartment has been extensively analyzed and has revealed the presence of precise, fine-tuned mechanisms that control the levels and accessibility to substrates of LAMP-2A at the lysosomal membrane (Fig. 1). CMA activity is directly proportional to the number of
Activation of CMA during starvation
The first stimulus shown to activate CMA was nutritional starvation (Fig. 2A). Removal of serum in cultured cells for more than 10 h, or prolonged starvation in animals (for up to 3 days), increase CMA activity and reduce the cellular content of KFERQ-containing proteins [21], [34]. Starvation-induced activation of CMA coincides with the decay in macroautophagy [12], [13]. Cells might benefit from switching to a more selective degradation, such that particular essential proteins could be
CMA and aging
Total rates of protein degradation decline with age in almost all tissues and organisms analyzed (from senescent fibroblasts in culture to fruit flies, nematodes, and mammals) (reviewed in [38]). In fact, reduced proteolytic capacity with age has been proposed to be responsible for the higher content of altered proteins and damaged organelles in old organisms. Quantitative and qualitative changes with age have been described for both the ubiquitin–proteasome system and lysosomes, and CMA is no
CMA and disease
Conditions resulting in a primary defect in the lysosomal system may secondarily affect CMA activity. However, there are also a series of disorders in which dysfunction of CMA seems to directly contribute to their pathogenesis.
The potential role of CMA dysfunction in neurodegenerative diseases is currently a subject of increasing interest. Many of these diseases involve the aberrant accumulation of protein inclusions or aggregates in the cytosol of the affected neurons [42]. The intrinsic
Concluding remarks and pending questions
The unique characteristics of CMA – selectivity and direct translocation of substrate proteins across the lysosomal membrane – dictate the nature of the substrates for this autophagic pathway and determine the contribution of CMA to different aspects of cell physiology.
Despite the considerable advances in the molecular dissection of this pathway in recent years, there are still many pieces missing from the CMA “puzzle”. For instance, it remains unclear whether other organisms (besides mammals)
Acknowledgements
Work in our laboratory is supported by NIH grants from NIA (AG021904, AG031782), NIDKK (DK041918), NINDS (NS038370), a Glenn Foundation Award and a Hirsch/Weill-Caulier Career Scientist Award. S.J.O. is supported by a NIH/NIA training grant T32 AG023475.
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