Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways

被引:50
作者
Herman-Bachinsky, Y.
Ryoo, H. -D.
Ciechanover, A.
Gonen, H.
机构
[1] Technion Israel Inst Technol, Canc & Vasc Biol Res Ctr, Rappaport Fac Med, IL-31096 Haifa, Israel
[2] Technion Israel Inst Technol, Res Inst, IL-31096 Haifa, Israel
[3] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA
基金
以色列科学基金会;
关键词
IAP; ubiquitin; degradation; N-end rule; apoptosis; Caspase; Drosophila; END RULE PATHWAY; INHIBITOR DIAP1; PROTEIN LIGASE; CELL-SURVIVAL; TRANSFER-RNA; APOPTOSIS; DEGRADATION; REAPER; HID; GRIM;
D O I
10.1038/sj.cdd.4402079
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
Inhibitors of apoptosis proteins (IAPs) suppress cell death by inactivating proapoptotic regulators, and therefore play important roles in controlling apoptosis in normal and malignant cells. Many IAPs are ubiquitin ligases, and their activity is mediated via ubiquitination and subsequent degradation of their targets. Here we corroborate a previous observation that DIAP1 (Drosophila IAP1) can be degraded via a two-step mechanism: (i) limited caspase-mediated cleavage and (ii) degradation of the released fragment via the ubiquitin N-end rule pathway. Yet, we demonstrate that this pathway is not the only one involved in DIAP1 degradation, and the intact protein can be degraded independent of prior caspase cleavage. Importantly, this mode of degradation does not require the RING-finger-mediated autoubiquitinating activity of DIAP1, believed to target many RING-finger E3s for self-destruction. Our preliminary data suggest that DIAP2 mediates DIAP1 degradation, suggesting a novel regulatory loop within the apoptotic pathway. Studying the role of the autoubiquitinating activity of DIAP1, we demonstrate that it does not involve formation of Lys48-based polyubiquitin chains, but probably chains linked via Lys63. Our preliminary data suggest that the autoubiquitination serves to attenuate the ligase activity of DIAP1 towards its exogenous substrates.
引用
收藏
页码:861 / 871
页数:11
相关论文
共 46 条
[1]   The ubiquitin ligase HectH9 regulates transcriptional activation by myc and is essential for tumor cell proliferation [J].
Adhikary, S ;
Marinoni, F ;
Hock, A ;
Hulleman, E ;
Popov, N ;
Beier, R ;
Bernard, S ;
Quarto, M ;
Capra, M ;
Goettig, S ;
Kogel, U ;
Scheffner, M ;
Helin, K ;
Eilers, M .
CELL, 2005, 123 (03) :409-421
[2]   Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A [J].
Andersen, PL ;
Zhou, HL ;
Pastushok, L ;
Moraes, T ;
McKenna, S ;
Ziola, B ;
Ellison, MJ ;
Dixit, VM ;
Xiao, W .
JOURNAL OF CELL BIOLOGY, 2005, 170 (05) :745-755
[3]   THE DEGRADATION SIGNAL IN A SHORT-LIVED PROTEIN [J].
BACHMAIR, A ;
VARSHAVSKY, A .
CELL, 1989, 56 (06) :1019-1032
[4]   INVIVO HALF-LIFE OF A PROTEIN IS A FUNCTION OF ITS AMINO-TERMINAL RESIDUE [J].
BACHMAIR, A ;
FINLEY, D ;
VARSHAVSKY, A .
SCIENCE, 1986, 234 (4773) :179-186
[5]   YEAST N-TERMINAL AMIDASE - A NEW ENZYME AND COMPONENT OF THE N-END RULE PATHWAY [J].
BAKER, RT ;
VARSHAVSKY, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (20) :12065-12074
[6]   Binding and recognition in the assembly of an active BRCA1 /BARD1 ubiquitin-ligase complex [J].
Brzovic, PS ;
Keeffe, JR ;
Nishikawa, H ;
Miyamoto, K ;
Fox, D ;
Fukuda, M ;
Ohta, T ;
Klevit, R .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (10) :5646-5651
[7]   Molecular mechanism of Reaper-Grim-Hid-mediated suppression of DIAP1-dependent Dronc ubiquitination [J].
Chai, JJ ;
Yan, N ;
Huh, JR ;
Wu, JW ;
Li, WY ;
Hay, BA ;
Shi, YG .
NATURE STRUCTURAL BIOLOGY, 2003, 10 (11) :892-898
[8]  
CIECHANOVER A, 1988, J BIOL CHEM, V263, P11155
[9]   c-IAP1 is cleaved by caspases to produce a proapoptotic C-terminal fragment [J].
Clem, RJ ;
Sheu, TT ;
Richter, BWM ;
He, WW ;
Thornberry, NA ;
Duckett, CS ;
Hardwick, JM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (10) :7602-7608
[10]   Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain [J].
Deng, L ;
Wang, C ;
Spencer, E ;
Yang, LY ;
Braun, A ;
You, JX ;
Slaughter, C ;
Pickart, C ;
Chen, ZJ .
CELL, 2000, 103 (02) :351-361