Bimodal protein targeting through activation of cryptic mitochondrial targeting signals by an inducible cytosolic endoprotease.
Bimodal targeting of the endoplasmic reticular protein, cytochrome P4501A1 (CYP1A1), to mitochondria involves activation of a cryptic mitochondrial targeting signal through endoprotease processing of the protein. Here, we characterized the endoprotease that regulates mitochondrial targeting of CYP1A1. The endoprotease, which was induced by beta-naphthoflavone, was a dimer of 90 kDa and 40 kDa subunits, each containing Ser protease domains. The purified protease processed CYP1A1 in a sequence-specific manner, leading to its mitochondrial import. The glucocorticoid receptor, retinoid X receptor, and p53 underwent similar processing-coupled mitochondrial transport. The inducible 90 kDa subunit was a limiting factor in many cells and some tissues and, thus, regulates the mitochondrial levels of these proteins. A number of other mitochondria-associated proteins with noncanonical targeting signals may also be substrates of this endoprotease. Our results describe a new mechanism of mitochondrial protein import that requires an inducible cytoplasmic endoprotease for activation of cryptic mitochondrial targeting signals.
Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ettickan
E
Boopathi
Satish
S
Srinivasan
Ji-Kang
JK
Fang
Narayan G
NG
Avadhani
D000818:Animals; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008970:Molecular Weight; D010447:Peptide Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013379:Substrate Specificity; D019324:beta-Naphthoflavone / Q000494:pharmacology
D021122:Protein Subunits; D034741:RNA, Small Interfering; D019324:beta-Naphthoflavone; D019363:Cytochrome P-450 CYP1A1; D010447:Peptide Hydrolases