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PNAS 102 (4): 1122-1126

Copyright © 2005 by the National Academy of Sciences.


IMMUNOLOGY

Drosophila peptidoglycan recognition protein LC (PGRP-LC) acts as a signal-transducing innate immune receptor

Kwang-Min Choe * {dagger}, Hyangkyu Lee {ddagger} §, and Kathryn V. Anderson *, ¶

*Developmental Biology Program, Sloan–Kettering Institute, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; and {ddagger}Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461

Edited by Frederick M. Ausubel, Harvard Medical School, Boston, MA, and approved November 30, 2004

Received for publication July 9, 2004.

Abstract: Drosophila peptidoglycan recognition protein LC (PGRP-LC), a transmembrane protein required for the response to bacterial infection, acts at the top of a cytoplasmic signaling cascade that requires the death-domain protein Imd and an I{kappa}B kinase to activate Relish, an NF-{kappa}B family member. It is not clear how binding of peptidoglycan to the extracellular domain of PGRP-LC activates intracellular signaling because its cytoplasmic domain has no homology to characterized proteins. Here, we demonstrate that PGRP-LC binds Imd and that its cytoplasmic domain is critical for its activity, suggesting that PGRP-LC acts as a signal-transducing receptor. The PGRP-LC cytoplasmic domain is also essential for the formation of dimers, and results suggest that dimerization may be required for receptor activation. The PGRP-LC cytoplasmic domain can mediate formation of heterodimers between different PGRP-LC isoforms, thereby potentially expanding the diversity of ligands that can be recognized by the receptor.

Key Words: Imd • innate immunity • NF-{kappa}B • Relish


Author contributions: K.-M.C. and K.V.A. designed research; K.-M.C. and H.L. performed research; K.-M.C. contributed new reagents/analytic tools; K.-M.C., H.L., and K.V.A. analyzed data; and K.-M.C. and K.V.A. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: PGRP, peptidoglycan-recognition protein; PAMP, pathogen-associated molecular pattern; TLR, Toll-like receptor; PRR, pattern-recognition receptor.

{dagger} Present address: Department of Neurobiology, Stanford University School of Medicine, 299 Campus Drive West, Stanford, CA 94305.

§ Present address: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305.

To whom correspondence should be addressed. E-mail: k-anderson{at}ski.mskcc.org.

© 2005 by The National Academy of Sciences of the USA


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