Caspase-mediated cleavage, IAP binding, and ubiquitination: linking three mechanisms crucial for Drosophila NF-kappaB signaling.
Innate immune responses are critical for the immediate protection against microbial infection. In Drosophila, infection leads to the rapid and robust production of antimicrobial peptides through two NF-kappaB signaling pathways-IMD and Toll. The IMD pathway is triggered by DAP-type peptidoglycan, common to most Gram-negative bacteria. Signaling downstream from the peptidoglycan receptors is thought to involve K63 ubiquitination and caspase-mediated cleavage, but the molecular mechanisms remain obscure. We now show that PGN stimulation causes caspase-mediated cleavage of the imd protein, exposing a highly conserved IAP-binding motif (IBM) at its neo-N terminus. A functional IBM is required for the association of cleaved IMD with the ubiquitin E3-ligase DIAP2. Through its association with DIAP2, IMD is rapidly conjugated with K63-linked polyubiquitin chains. These results mechanistically connect caspase-mediated cleavage and K63 ubiquitination in immune-induced NF-kappaB signaling.
Paquette
Nicholas
N
Division of Infectious Disease, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Broemer
Meike
M
Aggarwal
Kamna
K
Chen
Li
L
Husson
Marie
M
Ertürk-Hasdemir
Deniz
D
Reichhart
Jean-Marc
JM
Meier
Pascal
P
Silverman
Neal
N
D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D020169:Caspases / Q000502:physiology*; D004330:Drosophila / Q000201:enzymology* / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism* / Q000502:physiology; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D000099151:MAP Kinase Kinase Kinase 7
D020169:Caspases; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D044767:Ubiquitin-Protein Ligases; D000099151:MAP Kinase Kinase Kinase 7; C111892:DIAP2 protein, Drosophila; C439909:imd protein, Drosophila; C431887:dredd protein, Drosophila