Biogenesis, Structure and Function of Lysosomes
629
the vacuole requires distinct t-SNAREs, v-
SNAREs, and other membrane trafFcking
regulatory molecules.
W
h
e
t
h
e
ro
rn
o
tt
h
i
sp
a
t
hw
a
ye
x
i
s
t
s
in mammalian cells is not yet known.
It shares some mechanistic similarities
with chaperone-mediated autophagy. Nev-
ertheless, transport into vesicles prior to
lysosome/vacuole delivery of the proteins
remains a major difference in these two
protein-degradation pathways.
5.6
Chaperone-mediated Autophagy
This
lysosomal
pathway
of
proteolysis
is
activated
in
liver
and
other
mam-
malian tissues by prolonged starvation
(±ig. 5). Macroautophagy is activated early
in starvation but is subsequently sup-
pressed when Cma is activated. In cul-
tured Fbroblasts and other cultured cells,
macroautophagy is stimulated when cells
reach confluence. Withdrawal of serum
growth factors increases intracellular pro-
tein degradation due to Cma. However,
other
cell
types
in
culture
may
stim-
ulate macroautophagy and Cma simul-
taneously in response to withdrawal of
growth factors.
Approximately 30% of cytosolic proteins
are substrates for Cma. These proteins
contain peptide-targeting sequences bio-
chemically related to K±ERQ. Examples
of substrates of Cma include ribonuclease
A, glyceraldehydes-3-phosphate dehydro-
genase,
cytosolic
aspartate
aminotrans-
ferase, aldolase B, and certain annexin
isoforms, but not others. The K±ERQ
sequences
are
recognized
by
a
com-
plex of molecular chaperones including
hsc70. The substrate protein-hsc70 molec-
ular chaperone complex then binds to
LAMP2a. The substrate protein is unfolded
at the lysosomal surface presumably by
the molecular chaperone complex prior
to the protein’s entry into the lysosome
in a molecule-by-molecule process. The
substrate protein’s entry into lysosomes
requires an intralysosomal form of hsc70
presumably to pull the substrate protein
into the lysosome although the intralyso-
somal hsc70 may play other roles in Cma
as well. The substrate protein is rapidly
degraded in the lysosomal lumen.
6
Lysosomal Pathways of RNA Degradation
Lysosomes can also degrade RNA. Lyso-
somes are able to take up RNA, probably
by macroautophagy since the RNA uptake
by rat liver lysosomes increases in the ab-
sence of amino acids. It is interesting that
glucagon also stimulates macroautophagy
in the liver, but in this case protein, but
little RNA, is delivered to lysosomes for
degradation.
7
Lysosomal Storage Diseases
Mutations within genes encoding individ-
ual lysosomal enzymes can reduce their
targeting to lysosomes and/or their activ-
ities within lysosomes. Such mutations
result in the accumulation of materials
within
lysosomes, and
identifying
this
stored material is often critical for identify-
ing the missing enzyme activity (Table 1).
±or example, Tay-Sachs disease is associ-
ated with the lysosomal accumulation of
particular gangliosides due to the absence
of
β
-hexosaminidase. A more complicated
lysosomal storage disease results from
mutations in lysosomal cathepsin A. This
peptidase cleaves a major protein of the
previous page 629 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 631 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off