CNRS - AIX MARSEILLE UNIV: UMR7257

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Activation and regulation of the Drosophila Imd and JAK/STAT pathways

Heads Philippe LEONE

Coordinator: P Leone

The immune deficiency (IMD) pathway is mostly required in the host defense against Gram-negative bacteria [Lemaitre et al., 1995] and is triggered by pathogen recognition receptors (PRRs) of the peptidoglycan recognition protein (PGRP) family, namely PGRP-LC [Chloe et al, 2002] [Gottar et al., 2002] and PGRP-LE [Takehana et al., 2004].

Regulation of the IMD pathway by PGRP-LF [Basbous et al., 2011].

PGRP-LF is a specific negative regulator of the IMD pathway [Maillet et al., 2008]. PGRP-LF contains a 23-amino-acid intracellular tail, a transmembrane domain and two extracellular PGRP motifs (LFw and LFz). It was proposed that PGRP-LF acts as a decoy receptor by lowering the concentration of PGN. We have determined the crystal structure of the two PGRP domains constituting the ectodomain of PGRP-LF at 1.72 and 1.94 Å resolution. The structures show that the LFz and LFw domains do not have the classical PGN-docking groove that is found in other PGRP domains. Therefore they cannot directly interact with PGN, as confirmed by biochemical-binding assays. By using surface plasmon resonance (SPR) analysis, we showed that the PGRP-LF ectodomain interacts with the PGRP-LCx, the receptor of the IMD pathway. Thus, our results suggest a mechanism for downregulation of the IMD pathway based on the competition between PRGP-LCa and PGRP-LF for the binding to PGRP-LCx.

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Antiviral response [Coste et al., 2012]

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The Drosophila melanogaster gene CG11501 is up-regulated after septic injury and it has been shown that the JAK/STAT signaling pathway is involved in this induction [Boutros et al., 2002]. Furthermore, a genome-wide RNA interference screen in Drosophila cells identifies the CG11501 gene as a negative regulator of the JAK/STAT signaling pathway, although its precise molecular function is still unknown [Muller et al., 2005]. The CG11501 gene encodes a small cysteine-rich protein that we named Diedel. Diedel is 115 amino acids long and contains 10 cysteines. Strikingly, apart from Drosophila and the pea aphid Acyrthosiphon pisum, Diedel-related sequences were exclusively identified in insect DNA viruses of the Baculoviridae and Ascoviridae families. We have solved the crystal structure of Diedel at 1.15Å resolution by SIRAS using an iodo derivative. Diedel is composed of two sub domains SD1 and SD2. SD1 is made of an antiparallel β-sheet covered by an α-helix and displays a ferredoxin-like fold. SD2 reveals a new protein fold made of loops connected by four disulfide bridges. Further structural analysis identified conserved hydrophobic residues on the surface of Diedel that may constitute a potential binding site. The existence of two conformations, cis and trans, for the proline 52 may be of interest as prolyl peptidyl isomerisation has been shown to play a role in several physiological mechanisms. In conclusion we propose an extra cellular signaling function for Diedel, which is in accordance with its proposed role as negative regulator of the JAK/STAT signaling pathway.

Footnotes


[Lemaitre et al., 1995] Lemaitre B, Kromer-Metzger E, Michaut L, Nicolas E, Meister M, Georgel P, Reichhart JM, Hoffmann JA (1995) Proc Natl Acad Sci U S A 92 9465-9

[Chloe et al, 2002] Choe KM, Werner T, Stoven S, Hultmark D, Anderson KV (2002) Science 296 359-62

[Gottar et al., 2002] Gottar M, Gobert V, Michel T, Belvin M, Duyk G, Hoffmann JA, Ferrandon D, Royet J (2002) Nature 416 640-4

[Takehana et al., 2004] Takehana A, Yano T, Mita S, Kotani A, Oshima Y, Kurata S (2004) EMBO J 23 4690-700

[Basbous et al., 2011] Basbous N, Coste F, Leone P, Vincentelli R, Royet J, Kellenberger C, Roussel A (2011) EMBO Rep 12 327-33
2011
[Maillet et al., 2008] Maillet F, Bischoff V, Vignal C, Hoffmann J, Royet J (2008) Cell Host Microbe 3 293-303

[Coste et al., 2012] Nope
[Boutros et al., 2002] Boutros M, Agaisse H, Perrimon N (2002) Dev Cell 3 711-22

[Muller et al., 2005] Muller P, Kuttenkeuler D, Gesellchen V, Zeidler MP, Boutros M (2005) Nature 436 871-5
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