Lysosome membrane lipid microdomains: Novel regulators of chaperone-mediated autophagy

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble cytosolic proteins in lysosomes. The limiting step of this type of autophagy is the binding of substrates to the lysosome-associated membrane protein type 2A (LAMP-2A). In this work, we identify a dynamic subcompartmentalization of LAMP-2A in the lysosomal membrane, which underlies the molecular basis for the regulation of LAMP-2A function in CMA. A percentage of LAMP-2A localizes in discrete lysosomal membrane regions during resting conditions, but it exits these regions during CMA activation. Disruption of these regions by cholesterol-depleting agents or expression of a mutant LAMP-2A excluded from these regions enhances CMA activity, whereas loading of lysosomes with cholesterol significantly reduces CMA. Organization of LAMP-2A into multimeric complexes, required for translocation of substrates into lysosomes via CMA, only occurs outside the lipid-enriched membrane microdomains, whereas the LAMP-2A located within these regions is susceptible to proteolytic cleavage and degradation. Our results support that changes in the dynamic distribution of LAMP-2A into and out of discrete microdomains of the lysosomal membrane contribute to regulate CMA.

Original languageEnglish (US)
Pages (from-to)3921-3933
Number of pages13
JournalEMBO Journal
Volume25
Issue number17
DOIs
StatePublished - Sep 6 2006

Fingerprint

Lysosome-Associated Membrane Glycoproteins
Membrane Microdomains
Autophagy
Membrane Lipids
Lysosomes
Membranes
Cholesterol
Degradation
Substrates
Chemical activation
Lipids

Keywords

  • Autophagy
  • Lysosomes
  • Membrane microdomains
  • Proteases
  • Protein degradation

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Lysosome membrane lipid microdomains : Novel regulators of chaperone-mediated autophagy. / Kaushik, Susmita; Massey, Ashish C.; Cuervo, Ana Maria.

In: EMBO Journal, Vol. 25, No. 17, 06.09.2006, p. 3921-3933.

Research output: Contribution to journalArticle

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