TY - JOUR
T1 - Chaperone-Mediated Autophagy in Aging and Disease
AU - Massey, Ashish C.
AU - Zhang, Cong
AU - Cuervo, Ana Maria
N1 - Funding Information:
Research in our laboratory is supported by NIH/NIA grants AG021904 and AG19834, a Huntington's Disease Society of America Research grant and an Ellison Medical Foundation Award. ACM is supported by NIH training grant T32AG023475.
PY - 2006
Y1 - 2006
N2 - Different mechanisms target intracellular components for their degradation into lysosomes through what is known as autophagy. In mammals, three main forms of autophagy have been described: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). CMA is the only autophagic pathway that allows selective degradation of soluble proteins in lysosomes. In contrast to the other mammalian forms of autophagy, CMA does not require vesicle formation or major changes in the lysosomal membrane. Instead, substrate proteins directly cross the lysosomal membrane to reach the lumen, where they are rapidly degraded. The substrate proteins are targeted to the lysosomal membrane by recognition of a targeting motif (a KFERQ-like motif), by a chaperone complex, consisting of hsc70 and its cochaperones, in the cytoplasm. Once at the lysosomal membrane, the protein interacts with a lysosomal receptor for this pathway, lysosomal associated membrane protein type 2A (LAMP-2A), and it is translocated across the membrane into the lysosomal lumen assisted by a lysosome resident chaperone. These two characteristics-selectivity and direct substrate translocation-determine the particular role of CMA in different physiological and pathological conditions. In this chapter, we cover current findings on the molecular mechanisms for CMA and the possible pathophysiological relevance of this selective lysosomal degradation.
AB - Different mechanisms target intracellular components for their degradation into lysosomes through what is known as autophagy. In mammals, three main forms of autophagy have been described: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). CMA is the only autophagic pathway that allows selective degradation of soluble proteins in lysosomes. In contrast to the other mammalian forms of autophagy, CMA does not require vesicle formation or major changes in the lysosomal membrane. Instead, substrate proteins directly cross the lysosomal membrane to reach the lumen, where they are rapidly degraded. The substrate proteins are targeted to the lysosomal membrane by recognition of a targeting motif (a KFERQ-like motif), by a chaperone complex, consisting of hsc70 and its cochaperones, in the cytoplasm. Once at the lysosomal membrane, the protein interacts with a lysosomal receptor for this pathway, lysosomal associated membrane protein type 2A (LAMP-2A), and it is translocated across the membrane into the lysosomal lumen assisted by a lysosome resident chaperone. These two characteristics-selectivity and direct substrate translocation-determine the particular role of CMA in different physiological and pathological conditions. In this chapter, we cover current findings on the molecular mechanisms for CMA and the possible pathophysiological relevance of this selective lysosomal degradation.
UR - http://www.scopus.com/inward/record.url?scp=33745023775&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745023775&partnerID=8YFLogxK
U2 - 10.1016/S0070-2153(05)73007-6
DO - 10.1016/S0070-2153(05)73007-6
M3 - Review article
C2 - 16782460
AN - SCOPUS:33745023775
SN - 0070-2153
VL - 73
SP - 205
EP - 235
JO - Current Topics in Developmental Biology
JF - Current Topics in Developmental Biology
ER -