Selective degradation of annexins by chaperone-mediated autophagy.
Annexins are a family of proteins that bind phospholipids in a calcium-dependent manner. Analysis of the sequences of the different members of the annexin family revealed the presence of a pentapeptide biochemically related to KFERQ in some annexins but not in others. Such sequences have been proposed to be a targeting sequence for chaperone-mediated autophagy, a lysosomal pathway of protein degradation that is activated in confluent cells in response to removal of serum growth factors. We demonstrate that annexins II and VI, which contain KFERQ-like sequences, are degraded more rapidly in response to serum withdrawal, while annexins V and XI, without such sequences, are degraded at the same rate in the presence and absence of serum. Using isolated lysosomes, only the annexins containing KFERQ-like sequences are degraded by chaperone mediated-autophagy. Annexins V and XI could associate with lysosomes but did not enter the lysosomes and were not proteolytic substrates. Furthermore, four annexins containing KFERQ-like sequences, annexins I, II, IV, and VI, are enriched in lysosomes with high chaperone-mediated autophagy activity as expected for substrate proteins. These results provide striking evidence for the importance of KFERQ motifs in substrates of chaperone-mediated autophagy.
Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA. ana.cuervo@tufts.edu
A M
AM
Cuervo
A V
AV
Gomes
J A
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Barnes
J F
JF
Dice
D020816:Amino Acid Motifs; D000818:Animals; D017302:Annexins / Q000378:metabolism*; D002478:Cells, Cultured; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D018832:Molecular Chaperones / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D017302:Annexins; D018832:Molecular Chaperones