Reactivating chaperone-mediated autophagy: the advantages of preserving a selective autophagy
A.M. Cuervo
Albert Einstein College of Medicine, Departments of Anatomy and Structural Biology and of Development and Molecular Biology, 1300 Morris Park Avenue, Bronx, NY 10461, USA
We have previously identified a decrease with age in the activity of a
lysosomal pathway involved in the selective degradation of soluble
cytosolic proteins in most types of mammalian cells. This autophagic
pathway, known as chaperone-mediated autophagy (CMA), is preferentially
activated under stress conditions such as nutritional stress or
exposure to different toxic derivatives. Under these conditions, an
amino acid motif in the substrate proteins is recognized by a cytosolic
chaperone complex, which targets the substrate to the lysosomal
membrane. After docking on a receptor protein at the membrane, the
substrate is unfolded and crosses the lysosomal membrane assisted by a
luminal resident chaperone. Once translocated, the substrate protein is
rapidly degraded by the lysosomal hydrolases. The ability of cells to
upregulate CMA in response to these stressors decreases as they age,
likely resulting in poor removal of proteins normally degraded by this
autophagic pathway. We have identified a decrease with age in the
levels of the CMA receptor as the primary defect responsible for CMA
failure.
The main peculiarity of CMA, when compared to other forms of autophagy,
is its selectivity. Only soluble proteins containing the CMA targeting
motif are degraded through this pathway. This selectivity confers CMA
the ability to remove particular proteins from inside cells without
altering neighboring ones. In fact, we have found that activation of
CMA is part of the defensive response orchestrated by most cells during
oxidative injury. Oxidizing conditions promote higher rates of CMA by
affecting both the substrates and the lysosomal compartment directly.
Oxidized substrates are more efficiently internalized into lysosomes
and, independent of this effect on the substrates, lysosomes from cells
exposed to mild-oxidative stress also show enhanced ability for
substrate translocation. This novel role of CMA in the removal of
oxidized cytosolic proteins during mild-oxidative stress reinforces the
contribution of the age-related failure in CMA to accumulation of
damaged proteins in old tissues. In fact, in livers from old rodents,
we have found a striking correlation between the increase in the levels
of oxidized proteins in the cytosol as the animal ages and the decrease
in the amount of oxidized proteins detected inside CMA active
lysosomes.
Our group has undertaken two different approaches to restore CMA in old
rodents. On one hand, we have generated a bitransgenic mouse line in
which levels of the CMA receptor at the lysosomal membrane can be
regulated at wish. By preventing the decrease in the receptor levels
with age, we intend to maintain proper CMA activity in old rodents. As
a second approach we are investigating the effect of caloric
restriction on CMA activity. We have found a constitutive activation of
this autophagic pathway in caloric restricted rodents till advanced
ages. This continuous activation of CMA may contribute to the proper
removal of oxidized and other damaged proteins in these animals. These
two interventions to enhance CMA activity should allow us in the future
to analyze possible beneficial effects of the restoration of this form
of autophagy in old organisms.
Key words:
autophagy, lysosomes, oxidation, chaperones, proteolysis
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