Unique pathologies resulting from autophagy and lysosome inhibition

Inhibition of lysosomal degradation can lead to death and injury of normal cells as a result of compromised type II cell death. The developmental clearing of a large tissue mass such as the larval salivary glands of Drosophila melanogaster involves Type II cell death, which is a type of apoptosis where the apoptotic bodies are delivered to lysosomes for degradation by autophagy1. If the lysosomes are unable to break down the protein aggregates of the apoptotic bodies then they remain in the extracellular matrix (ECM) of surrounding cells and cause toxicity possibly by inducing inflammation and aberrant signalling with carcinogenic effects.

Starvation survival is reduced in cells unable to degrade non-essential proteins via the lysosome1. Under starvation conditions proteins with the KFERQ amino acid sequence are targeted to the lysosome for degradation. The proteolysis of non-essential proteins releases energy for cell to utilise in essential pathways. Therefore under starvation conditions lysosomal protein degradation is essential.

Cells without functional autophagy age much faster2. Reactive oxygen species generated by defective mitochondria or peroxisomes result in DNA damage associated with aging. Mitochondria or peroxisomes with an active production of oxygen reactive species or with alteration in their membrane potential are preferentially sequestered by autophagic vacuoles. This organelle turnover prevents the generation of DNA damaging reactive oxygen species from defective organelles.

Extracellular signalling is directly affected by the degradation of transmembrane receptors by the lysosome. The lysosome is the main degradation pathway for transmembrane proteins. Lysosome inhibition leads to inappropriate signalling. For example TGF-β receptors are down regulated after prolonged stimulation by endocytosis via autophagosomes with subsequent lysosomal degradation3.

Refs

  1. Mariño, G. and López-Otín, C. 2004. Autophagy: molecular mechanisms, physiological functions and relevance in human pathology. Cell Mol Life Sci. 61:1439-1454.
  1. Levine, B. and Klionsky, D.J. 2004. Development by Self-Digestion: Molecular Mechanisms and Biological Functions of Autophagy. Dev Cell. 6:463-477.
  1. Runyan, C.E. Poncelet, A-C. Schnaper, H.W. 2006. TGF-β receptor-binding proteins: Complex interactions. Cellular Signalling. 18:2077-2088.
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