rudra interrupts receptor signaling complexes to negatively regulate the imd pathway楼陀罗中断受体信号复合物负调节imd通路.pdfVIP

Rudra Interrupts Receptor Signaling Complexes to Negatively Regulate the IMD Pathway ¨ Kamna Aggarwal, Florentina Rus, Christie Vriesema-Magnuson, Deniz Erturk-Hasdemir, Nicholas Paquette, Neal Silverman* Divison of Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America Abstract Insects rely primarily on innate immune responses to fight pathogens. In Drosophila, antimicrobial peptides are key contributors to host defense. Antimicrobial peptide gene expression is regulated by the IMD and Toll pathways. Bacterial peptidoglycans trigger these pathways, through recognition by peptidoglycan recognition proteins (PGRPs). DAP-type peptidoglycan triggers the IMD pathway via PGRP-LC and PGRP-LE, while lysine-type peptidoglycan is an agonist for the Toll pathway through PGRP-SA and PGRP-SD. Recent work has shown that the intensity and duration of the immune responses initiating with these receptors is tightly regulated at multiple levels, by a series of negative regulators. Through two-hybrid screening with PGRP-LC, we identified Rudra, a new regulator of the IMD pathway, and demonstrate that it is a critical feedback inhibitor of peptidoglycan receptor signaling. Following stimulation of the IMD pathway, rudra expression was rapidly induced. In cells, RNAi targeting of rudra caused a marked up-regulation of antimicrobial peptide gene expression. rudra mutant flies also hyper-activated antimicrobial peptide genes and were more resistant to infection with the insect pathogen Erwinia carotovora carotovora. Molecularly, Rudra was found to bind and interfere with both PGRP-LC and PGRP- LE, disrupting their signaling complex. These r