Review
Chaperone-mediated autophagy: Molecular mechanisms and physiological relevance

https://doi.org/10.1016/j.semcdb.2010.02.005Get rights and content

Abstract

Chaperone-mediated autophagy (CMA) is a selective lysosomal pathway for the degradation of cytosolic proteins. We review in this work some of the recent findings on this pathway regarding the molecular mechanisms that contribute to substrate targeting, binding and translocation across the lysosomal membrane. We have placed particular emphasis on the critical role that changes in the lipid composition of the lysosomal membrane play in the regulation of CMA, as well as the modulatory effect of other novel CMA components. In the second part of this review, we describe the physiological relevance of CMA and its role as one of the cellular mechanisms involved in the response to stress. Changes with age in CMA activity and the contribution of failure of CMA to the phenotype of aging and to the pathogenesis of several age-related pathologies are also described.

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.

References (53)

  • T. Kabuta et al.

    Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy

    J Biol Chem

    (2008)
  • A. Cuervo et al.

    Direct lysosomal uptake of α2-microglobulin contributes to chemically induced nephropathy

    Kidney Int

    (1999)
  • S. Sooparb et al.

    Suppression of chaperone-mediated autophagy in the renal cortex during acute diabetes mellitus

    Kidney Int

    (2004)
  • A. Ciechanover

    Intracellular protein degradation: from a vague idea through the lysosome and the ubiquitin–proteasome system and onto human diseases and drug targeting

    Hematol Am Soc Hematol Educ Program

    (2006)
  • E. Knecht et al.

    Intracellular protein degradation in mammalian cells: recent developments

    Cell Mol Life Sci

    (2009)
  • A.L. Goldberg

    Protein degradation and protection against misfolded or damaged proteins

    Nature

    (2003)
  • V. Deretic

    Links between autophagy, innate immunity, inflammation and Crohn's disease

    Dig Dis

    (2009)
  • D. Finley

    Recognition and processing of ubiquitin–protein conjugates by the proteasome

    Annu Rev Biochem

    (2009)
  • C. He et al.

    Regulation mechanisms and signaling pathways of autophagy

    Annu Rev Genet

    (2009)
  • N. Mizushima et al.

    Autophagy fights disease through cellular self-digestion

    Nature

    (2008)
  • J. Dice

    Lysosomal pathways of protein degradation

    (2000)
  • J. Dice

    Chaperone-mediated autophagy

    Autophagy

    (2007)
  • A.M. Cuervo

    Chaperone-mediated autophagy: selectivity pays off

    Trends Endocrinol Metab

    (2009)
  • G. Fuertes et al.

    Changes in the proteolytic activities of proteasomes and lysosomes in human fibroblasts produced by serum withdrawal, amino-acid deprivation and confluent conditions

    Biochem J

    (2003)
  • A.C. Massey et al.

    Consequences of the selective blockage of chaperone-mediated autophagy

    Proc Nat Acad Sci USA

    (2006)
  • J. Dice

    Peptide sequences that target cytosolic proteins for lysosomal proteolysis

    Trends Biochem Sci

    (1990)
  • Cited by (0)

    View full text