Early cellular changes after blockage of chaperone-mediated autophagy

Ashish C. Massey, Antonio Follenzi, Roberta Kiffin, Cong Zhang, Ana Maria Cuervo

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Cytosolic proteins can be selectively degraded in lysosomes by chaperone-mediated autophagy (CMA), an autophagic pathway maximally activated under stress. In previous works we have demonstrated the existence of a cross-talk between CMA and macroautophagy, the other stress-related autophagic pathway responsible for the "in bulk" degradation of whole regions of the cytosol and for organelle turnover. We found that chronic blockage of CMA, as the one described in aging cells, results in constitutive activation of macroautophagy, supporting that one pathway may compensate for the other. In this work we have investigated the series of early cellular events that precede the activation of macroautophagy upon CMA blockage and the consequences of this blockage on cellular homeostasis. Shortly after CMA blockage, we have found functional alterations in macroautophagy and the ubiquitin-proteasome system, that are progressively corrected as CMA blockage persists. Basal macroautophagic activity remains initially unaltered, but we observed a delay in its activation in response to serum removal, a well characterized inducer for this pathway. Slower degradation of short-lived proteins, and a transient decrease in some of the proteasome proteolytic activities are also evident in the first stages of CMA blockage. This global alteration of the proteolytic systems supports the coordinated functioning of all of them, and seems responsible for the intracellular accumulation of altered proteins. Based on the time-course of the cellular changes, we propose that a minimal threshold of these toxic products needs to accumulate in order to constitutively activate macroautophagy and thus return cellular homeostasis to normal.

Original languageEnglish (US)
Pages (from-to)442-456
Number of pages15
JournalAutophagy
Volume4
Issue number4
StatePublished - May 16 2008

Fingerprint

Autophagy
Proteasome Endopeptidase Complex
Homeostasis
Proteins
Cell Aging
Poisons
Ubiquitin
Lysosomes
Organelles
Cytosol

Keywords

  • Autophagy
  • Chaperones
  • Lysosomal degradation
  • Macroautophagy
  • Proteasome
  • Protein aggregates

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Massey, A. C., Follenzi, A., Kiffin, R., Zhang, C., & Cuervo, A. M. (2008). Early cellular changes after blockage of chaperone-mediated autophagy. Autophagy, 4(4), 442-456.

Early cellular changes after blockage of chaperone-mediated autophagy. / Massey, Ashish C.; Follenzi, Antonio; Kiffin, Roberta; Zhang, Cong; Cuervo, Ana Maria.

In: Autophagy, Vol. 4, No. 4, 16.05.2008, p. 442-456.

Research output: Contribution to journalArticle

Massey, AC, Follenzi, A, Kiffin, R, Zhang, C & Cuervo, AM 2008, 'Early cellular changes after blockage of chaperone-mediated autophagy', Autophagy, vol. 4, no. 4, pp. 442-456.
Massey AC, Follenzi A, Kiffin R, Zhang C, Cuervo AM. Early cellular changes after blockage of chaperone-mediated autophagy. Autophagy. 2008 May 16;4(4):442-456.
Massey, Ashish C. ; Follenzi, Antonio ; Kiffin, Roberta ; Zhang, Cong ; Cuervo, Ana Maria. / Early cellular changes after blockage of chaperone-mediated autophagy. In: Autophagy. 2008 ; Vol. 4, No. 4. pp. 442-456.
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