Summary
CMA is a selective autophagy pathway where cytosolic proteins containing KFERQ-like motifs are recognized by Hsc70, delivered to lysosomes via LAMP-2A, and degraded. Unlike macroautophagy, CMA directly translocates substrates without vesicle formation.
Key Points
- 1CMA uses KFERQ-like motifs for substrate selection by Hsc70
- 2LAMP-2A multimerizes to form translocation channel
- 3Substrates must unfold to cross the lysosomal membrane
- 4CMA declines with aging, contributing to neurodegeneration
- 5Distinct from macroautophagy: no vesicle formation
Chaperone-mediated autophagy (CMA) is a highly selective protein degradation pathway that directly translocates cytosolic proteins into lysosomes for breakdown.
The KFERQ Motif
CMA selectivity depends on a targeting signal:
- Pentapeptide motif: KFERQ or biochemically related sequences
- Recognized by the cytosolic chaperone Hsc70 (constitutive Hsp70)
Molecular Machinery
Substrate Recognition
Lysosomal Docking
- LAMP-2A (Lysosomal-Associated Membrane Protein 2A) is the receptor
Translocation and Degradation
Regulation
CMA activity is modulated by:
- Nutritional status: Upregulated during prolonged starvation
- Oxidative stress: Increases to remove damaged proteins
- Aging: CMA declines, contributing to protein accumulation
- Lipid composition: Lysosomal membrane lipids affect LAMP-2A dynamics
Physiological Functions
- Amino acid recycling during nutrient deprivation
- Quality control: Removes oxidized and damaged proteins
- Metabolism regulation: Degrades key metabolic enzymes (GAPDH, PKM2)
- Transcription factor control: Regulates HIF-1α and c-Myc levels
Disease Connections
- Neurodegeneration: α-synuclein and tau are CMA substrates; pathological forms block translocation
- Aging: Progressive CMA decline accelerates protein aggregation
- Cancer: Tumor cells often have elevated CMA to cope with metabolic stress
- Lysosomal storage disorders: LAMP-2 mutations cause Danon disease