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.
Boopathi
Ettickan
E
Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Srinivasan
Satish
S
Fang
Ji-Kang
JK
Avadhani
Narayan G
NG
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