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Sci Signal. 2015 Oct 27;8(400):ra107. doi: 10.1126/scisignal.2005971.

Genome-wide RNAi screening implicates the E3 ubiquitin ligase Sherpa in mediating innate immune signaling by Toll in Drosophila adults.

Author information

1
Division of Molecular Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
2
Division of Molecular Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan. Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo 102-0076, Japan. takayuki.kuraishi@gmail.com kurata@mail.pharm.tohoku.ac.jp.
3
Division of Molecular Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan. takayuki.kuraishi@gmail.com kurata@mail.pharm.tohoku.ac.jp.

Abstract

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 κB (NF-κB) homolog Dif, or we knocked down Cactus, the Drosophila homolog of mammalian inhibitor of NF-κB. 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.

PMID:
26508789
DOI:
10.1126/scisignal.2005971
[Indexed for MEDLINE]

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