Abstract
Drosophila immune deficiency (IMD) pathway is similar to the human tumor necrosis factor receptor (TNFR) signaling pathway and is preferentially activated by Gram-negative bacterial infection. Recent studies highlighted the importance of IMD pathway regulation as it is tightly controlled by numbers of negative regulators at multiple levels. Here, we report a new negative regulator of the IMD pathway, Verloren (Velo). Silencing of Velo led to constitutive expression of the IMD pathway dependent antimicrobial peptides (AMPs), and Escherichia coli stimulation further enhanced the AMP expression. Epistatic analysis indicated that Velo knock-down mediated AMP upregulation is dependent on the canonical members of the IMD pathway. The immune fluorescent study using overexpression constructs revealed that Velo resides both in the nucleus and cytoplasm, but the majority (~ 75%) is localized in the nucleus. We also observed from in vivo analysis that Velo knock-down flies exhibit significant upregulation of the AMP expression and reduced bacterial load. Survival experiments showed that Velo knock-down flies have a short lifespan and are susceptible to the infection of pathogenic Gram-negative bacteria, P. aeruginosa. Taken together, these data suggest that Velo is an additional new negative regulator of the IMD pathway, possibly acting in both the nucleus and cytoplasm.
Highlights
Drosophila immune deficiency (IMD) pathway is similar to the human tumor necrosis factor receptor (TNFR) signaling pathway and is preferentially activated by Gram-negative bacterial infection
We observed a similar upregulation of endogenous antimicrobial peptides (AMPs), namely Attacin, Diptericin, and Metchnikowin (Fig. 1C–E), further confirming that Velo knock-down triggers the induction of the IMD pathway dependent antimicrobial peptide expression at both basal and immune-stimulated conditions
We observed that knock-down of Velo in flies led to a partial lethality at larval/pupal stage, reduced lifespan and high susceptibility to P. aeruginosa infection
Summary
Drosophila immune deficiency (IMD) pathway is similar to the human tumor necrosis factor receptor (TNFR) signaling pathway and is preferentially activated by Gram-negative bacterial infection. Survival experiments showed that Velo knock-down flies have a short lifespan and are susceptible to the infection of pathogenic Gram-negative bacteria, P. aeruginosa Taken together, these data suggest that Velo is an additional new negative regulator of the IMD pathway, possibly acting in both the nucleus and cytoplasm. Diaminopimelic acid-type peptidoglycan (DAP-type PGN), which is common to most Gram-negative bacteria, to the peptidoglycan recognition protein long-type C (PGRP-LC) and PGRP-LE r eceptors[23,24,25] This ligand-receptor binding induces the adaptor complex composed of death domain containing IMD12,26, Fas-associated death domain (FADD)[27,28], and Death related ced-3/Nedd2-like caspase (DREDD)[29]. These results suggest that the SUMOylation plays a critical role in the activation of the IMD pathway[54]
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