Journal
SCIENCE SIGNALING
Volume 8, Issue 400, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2005971
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Funding
- Japan Science and Technology Agency
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Program for the Promotion of Basic Research Activities for Innovative Biosciences
- Global COE Research Grant (Tohoku University Ecosystem Adaptability)
- Takeda Science Foundation
- Kao Foundation for Arts and Sciences
- Uehara Memorial Foundation
- Futaba Electronics Memorial Foundation
- Grants-in-Aid for Scientific Research [15K18855] Funding Source: KAKEN
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The Drosophila Toll pathway plays important roles in innate immune responses against Gram-positive bacteria and fungi. To identify previously uncharacterized components of this pathway, we performed comparative, ex vivo, genome-wide RNA interference screening. In four screens, we overexpressed the Toll adaptor protein dMyd88, the downstream kinase Pelle, or the nuclear factor kappa B (NF-kappa B) homolog Dif, or we knocked down Cactus, the Drosophila homolog of mammalian inhibitor of NF-kappa B. On the basis of these screens, we identified the E3 ubiquitin ligase Sherpa as being necessary for the activation of Toll signaling. A loss-of-function sherpa mutant fly exhibited compromised production of antimicrobial peptides and enhanced susceptibility to infection by Gram-positive bacteria. In cultured cells, Sherpa mediated ubiquitylation of dMyd88 and Sherpa itself, and Sherpa and Drosophila SUMO (small ubiquitin-like modifier) were required for the proper membrane localization of an adaptor complex containing dMyd88. These findings highlight a role for Sherpa in Drosophila host defense and suggest the SUMOylation-mediated regulation of dMyd88 functions in Toll innate immune signaling.
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