Identification of regulators of chaperone-mediated autophagy.
Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of cytosolic proteins in lysosomes that contributes to cellular quality control and becomes an additional source of amino acids when nutrients are scarce. A chaperone complex delivers CMA substrates to a receptor protein at the lysosomal membrane that assembles into multimeric translocation complexes. However, the mechanisms regulating this process remain, for the most part, unknown. In this work, we have identified two regulatory proteins, GFAP and EF1alpha, that mediate a previously unknown inhibitory effect of GTP on CMA. GFAP stabilizes the multimeric translocation complex against chaperone-mediated disassembly, whereas GTP-mediated release of EF1alpha from the lysosomal membrane promotes self-association of GFAP, disassembly of the CMA translocation complex, and the consequent decrease in CMA. The dynamic interactions of these two proteins at the lysosomal membrane unveil now a role for GTP as a negative regulator of CMA.
Bandyopadhyay
Urmi
U
Department of Development and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Sridhar
Sunandini
S
Kaushik
Susmita
S
Kiffin
Roberta
R
Cuervo
Ana Maria
AM
D000818:Animals; D001343:Autophagy; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein; D006160:Guanosine Triphosphate / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D046912:Multiprotein Complexes; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020648:Peptide Elongation Factor 1 / Q000378:metabolism; D021381:Protein Transport; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014162:Transfection
D005904:Glial Fibrillary Acidic Protein; D052119:Lysosomal-Associated Membrane Protein 2; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D020648:Peptide Elongation Factor 1; C528900:glial fibrillary astrocytic protein, mouse; D006160:Guanosine Triphosphate
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