The host antimicrobial immune response relies on a complex interplay of molecular mechanisms to effectively combat microbial infections.Herein,we investigate the functional role of Cullin-3(Cul3),one critical constitu...The host antimicrobial immune response relies on a complex interplay of molecular mechanisms to effectively combat microbial infections.Herein,we investigate the functional role of Cullin-3(Cul3),one critical constituent of Cullin-RING ubiquitin ligases,in the Drosophila melanogaster(fruit fly)antimicrobial immune defense.Weshow that silencing of Cul3 leads to a decreased induction of antimicrobial peptides and high mortality in adult flies after bacterial infection.Through biochemical approaches,we demonstrate that Cul3 predominantly relies on its BTB-binding domain and neddylation domain to physically associate with death-associated inhibitor of apoptosis 2(Diap2).Importantly,Cul3 ameliorates the Diap2-mediated ubiquitination of death-related ced-3/Nedd2-like caspase(Dredd),a process essential for robust immune deficiency signaling upon bacterial infection.Taken together,our findings highlight a previously unrecognized regulatory axis of Cul3/Diap2/Dredd in the fly antimicrobial immune defense,providing potential insights into therapeutic strategies for combating bacterial infections in humans.展开更多
基金supported by grants from the National Natural Science Foundation of China(32100702).
文摘The host antimicrobial immune response relies on a complex interplay of molecular mechanisms to effectively combat microbial infections.Herein,we investigate the functional role of Cullin-3(Cul3),one critical constituent of Cullin-RING ubiquitin ligases,in the Drosophila melanogaster(fruit fly)antimicrobial immune defense.Weshow that silencing of Cul3 leads to a decreased induction of antimicrobial peptides and high mortality in adult flies after bacterial infection.Through biochemical approaches,we demonstrate that Cul3 predominantly relies on its BTB-binding domain and neddylation domain to physically associate with death-associated inhibitor of apoptosis 2(Diap2).Importantly,Cul3 ameliorates the Diap2-mediated ubiquitination of death-related ced-3/Nedd2-like caspase(Dredd),a process essential for robust immune deficiency signaling upon bacterial infection.Taken together,our findings highlight a previously unrecognized regulatory axis of Cul3/Diap2/Dredd in the fly antimicrobial immune defense,providing potential insights into therapeutic strategies for combating bacterial infections in humans.
