Drosophila Morgue is an F box/ubiquitin conjugase domain protein important for grim-reaper mediated apoptosis.
In Drosophila melanogaster, apoptosis is controlled by the integrated actions of the Grim-Reaper (Grim-Rpr) and Drosophila Inhibitor of Apoptosis (DIAP) proteins (reviewed in refs 1 4). The anti-apoptotic DIAPs bind to caspases and inhibit their proteolytic activities. DIAPs also bind to Grim-Rpr proteins, an interaction that promotes caspase activity and the initiation of apoptosis. Using a genetic modifier screen, we identified four enhancers of grim-reaper-induced apoptosis that all regulate ubiquitination processes: uba-1, skpA, fat facets (faf), and morgue. Strikingly, morgue encodes a unique protein that contains both an F box and a ubiquitin E2 conjugase domain that lacks the active site Cys required for ubiquitin linkage. A reduction of morgue activity suppressed grim-reaper-induced cell death in Drosophila. In cultured cells, Morgue induced apoptosis that was suppressed by DIAP1. Targeted morgue expression downregulated DIAP1 levels in Drosophila tissue, and Morgue and Rpr together downregulated DIAP1 levels in cultured cells. Consistent with potential substrate binding functions in an SCF ubiquitin E3 ligase complex, Morgue exhibited F box-dependent association with SkpA and F box-independent association with DIAP1. Morgue may thus have a key function in apoptosis by targeting DIAP1 for ubiquitination and turnover.
Wing
John P
JP
Biology Department, University of Massachusetts at Amherst, Amherst, MA 01003, USA.
Schreader
Barbara A
BA
Yokokura
Takakazu
T
Wang
Yiqin
Y
Andrews
Paul S
PS
Huseinovic
Neda
N
Dong
Carolyn K
CK
Ogdahl
Justyne L
JL
Schwartz
Lawrence M
LM
White
Kristin
K
Nambu
John R
JR
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D004330:Drosophila; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins / Q000378:metabolism; D008025:Ligases / Q000737:chemistry* / Q000235:genetics; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D044843:SKP Cullin F-Box Protein Ligases; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes
C111891:DIAP1 protein, Drosophila; D029721:Drosophila Proteins; D005136:Eye Proteins; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D009479:Neuropeptides; D010455:Peptides; C434749:SkpA protein, Drosophila; D025801:Ubiquitin; C108881:grim protein, Drosophila; C460739:morgue protein, Drosophila; C086973:rpr protein, Drosophila; D044763:Ubiquitin-Conjugating Enzymes; D044843:SKP Cullin F-Box Protein Ligases; D008025:Ligases