Trends in Endocrinology & Metabolism
ReviewChaperone-mediated autophagy: selectivity pays off
Section snippets
Autophagy: cellular self-digestion with a purpose
We all probably invoke a very similar mental image in response to the word “lysosome”. I bet you just pictured a garbage container, didn’t you? This organelle has been associated with cellular cleaning almost since its description more than 50 years ago by Christian de Duve [1]. However, only recently has the importance of this cleaning function and its critical role in the maintenance of cellular homeostasis been appreciated in full. This improved understanding of the contribution of the
CMA: selective degradation moves to the lysosome
Although an accepted concept nowadays, the idea that single proteins could be picked up from the cytosol and shuttled to the lysosome for degradation in a selective manner was rather provocative when first postulated in the mid 1980s [9]. Selectivity was not a fit for lysosomal degradation, always perceived as an “in bulk” process. The initial idea originated from the observation that starvation in animals or serum removal in cultured cells beyond 8–10 h accelerated the degradation of particular
A tag and a chaperone are behind the selectivity of CMA
An essential requirement for a protein to become a CMA substrate is the presence of a pentapeptide motif biochemically related to KFERQ in its amino acid sequence [13] (Box 2). In fact, this motif, when mutated, prevents the degradation of proteins that otherwise would be degraded by this pathway. The recognition of this motif by a cytosolic chaperone leads to the delivery of the substrate protein to lysosomes. So far, HSC70, the constitutive member of the cytosolic family of chaperones of 70
A novel way of crossing the lysosomal membrane: look mom, no vesicles!
Once the cytosolic chaperone binds CMA substrates, it delivers them to lysosomes. Although the steps resulting in the appearance of the cytosolic cargo protein in the lysosomal lumen are not completely elucidated, it is well established that this process is clearly different from macro- and microautophagy in that delivery of substrates to the lysosomal lumen is saturable, it does not involve formation of vesiculations in the surface of the lysosomes and it requires unfolding of the substrate
Physiological functions of CMA
The first function proposed for CMA was to provide an alternative source of amino acids under conditions of prolonged starvation 9, 10, 24. Macroautophagy is activated in most cells during the first hours of starvation, reaches its maximum activity at around 6 h and then gradually declines 25, 26. CMA is activated when starvation persists beyond 6–8 h, reaches its maximum activity at around 24 h and remains activated for at least 3 days [24] (Figure 3). This switch from bulk degradation to a more
CMA and aging
The finding that CMA activity decreases with age [36], the identification of the main defect responsible for this functional decline [37] and the recent rescue of the CMA age-related defect in whole animals [38] provide strong support for the contribution of CMA failure to different aspects of aging [39].
The decrease in CMA activity with age was first described even before the molecular components for this pathway were characterized. Early studies in cultured primary fibroblasts revealed that
CMA and disease
Recently, malfunctioning of CMA has been linked to a growing number of human disorders [42]. The clue to the discovery that CMA activity was faulty in these pathologies has often been the detection of abnormally high levels of a CMA substrate protein in the affected cells (Figure 3).
Concluding remarks and future perspectives
During the past decade, a new appreciation for lysosomes and their multiple functions has emerged. In a short time, the mental image of this organelle has evolved from that of a mere “garbage disposal” to that of a sophisticated and active “recycling center”, a life-saver “energy boost for rainy days” and a complex “control panel” where cellular levels of specific proteins are regulated and the quality of proteins and organelles is controlled. The revival of the lysosomal system has lead to the
Acknowledgements
I thank my numerous colleagues in the field of autophagy who through their animated discussions have helped shape this review. I am in particular debt to Dr. Susmita Kaushik and Ms. Samantha Orenstein for critically reading the manuscript. Work in our laboratory is supported by National Institutes of Health grants from NIA (AG021904, AG031782), NIDKK (DK041918), NINDS (NS038370), a Glenn Foundation Award and a Hirsch/Weill-Caulier Career Scientist Award.
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