Self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL yields Pβ, a nuclear-targeted peptide

被引:54
作者
Sík, A
Passer, BJ
Koonin, EV
Pellegrini, L
机构
[1] Univ Laval, Ctr Rech Robert Giffard, Quebec City, PQ G1J 2G3, Canada
[2] Univ Laval, Dept Psychiat, Quebec City, PQ G1J 2G3, Canada
[3] Mol Engines Labs, F-75011 Paris, France
[4] Natl Lib Med, NCBI, NIH, Bethesda, MD 20894 USA
关键词
D O I
10.1074/jbc.M313756200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Regulated intramembrane proteolysis (RIP) is an emerging paradigm in signal transduction. RIP is mediated by intramembrane-cleaving proteases (I-CliPs), which liberate biologically active nuclear or secreted domains from their membrane-tethered precursor proteins. The yeast Pcp1p/Rbd1p protein is a Rhomboid-like I-CliP that regulates mitochondrial membrane remodeling and fusion through cleavage of Mgm1p, a regulator of these essential activities. Although this ancient function is conserved in PARL ((P) under bar resenilins-(a) under bar ssociated (R) double under bar homboid-(l) under bar ike protein), the mammalian ortholog of Pcp1p/Rbd1p, the two proteins show a strong divergence at their N termini. However, the N terminus of PARL is significantly conserved among vertebrates, particularly among mammals, suggesting that this domain evolved a distinct but still unknown function. Here, we show that the cytosolic N-terminal domain of PARL is cleaved at positions 52-53(alpha-site) and 77-78 (beta-site). Whereas alpha-cleavage is constitutive and removes the mitochondrial targeting sequence, beta-cleavage appears to be developmentally controlled and dependent on PARL I-CliP activity supplied in trans. The beta-cleavage of PARL liberates Pbeta, a nuclear targeted peptide whose sequence is conserved only in mammals. Thus, in addition to its evolutionarily conserved function in regulating mitochondrial dynamics, PARL might mediate a mammalian-specific, developmentally regulated mitochondria-to-nuclei signaling through regulated proteolysis of its N terminus and release of the Pbeta peptide.
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页码:15323 / 15329
页数:7
相关论文
共 33 条
[1]   RHOMBOID, A GENE REQUIRED FOR DORSOVENTRAL AXIS ESTABLISHMENT AND PERIPHERAL NERVOUS-SYSTEM DEVELOPMENT IN DROSOPHILA-MELANOGASTER [J].
BIER, E ;
JAN, LY ;
JAN, YN .
GENES & DEVELOPMENT, 1990, 4 (02) :190-203
[2]   Regulated intramembrane proteolysis: A control mechanism conserved from bacteria to humans [J].
Brown, MS ;
Ye, J ;
Rawson, RB ;
Goldstein, JL .
CELL, 2000, 100 (04) :391-398
[3]   A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood [J].
Brown, MS ;
Goldstein, JL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (20) :11041-11048
[4]   A transcriptively active complex of APP with Fe65 and histone acetyltransferase Tip60 [J].
Cao, XW ;
Südhof, TC .
SCIENCE, 2001, 293 (5527) :115-120
[5]  
CLAROS MG, 1995, COMPUT APPL BIOSCI, V11, P441
[6]   A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain [J].
De Strooper, B ;
Annaert, W ;
Cupers, P ;
Saftig, P ;
Craessaerts, K ;
Mumm, JS ;
Schroeter, EH ;
Schrijvers, V ;
Wolfe, MS ;
Ray, WJ ;
Goate, A ;
Kopan, R .
NATURE, 1999, 398 (6727) :518-522
[7]  
DeKoninck P, 1995, J NEUROSCI, V15, P7966
[8]   Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy [J].
Delettre, C ;
Lenaers, G ;
Griffoin, JM ;
Gigarel, N ;
Lorenzo, C ;
Belenguer, P ;
Pelloquin, L ;
Grosgeorge, J ;
Turc-Carel, C ;
Perret, E ;
Astarie-Dequeker, C ;
Lasquellec, L ;
Arnaud, B ;
Ducommun, B ;
Kaplan, J ;
Hamel, CP .
NATURE GENETICS, 2000, 26 (02) :207-210
[9]   A novel two-step mechanism for removal of a mitochondrial signal sequence involves the mAAA complex and the putative rhomboid protease Pcp1 [J].
Esser, K ;
Tursun, B ;
Ingenhoven, M ;
Michaelis, G ;
Pratje, E .
JOURNAL OF MOLECULAR BIOLOGY, 2002, 323 (05) :835-843
[10]   Acetylation regulates subcellular localization of the Wnt signaling nuclear effector POP-1 [J].
Gay, F ;
Calvo, D ;
Lo, MC ;
Ceron, J ;
Maduro, M ;
Lin, RL ;
Shi, Y .
GENES & DEVELOPMENT, 2003, 17 (06) :717-722