Caspase-mediated cleavage, IAP binding, and ubiquitination: linking three mechanisms crucial for Drosophila NF-kappaB signaling

Mol Cell. 2010 Jan 29;37(2):172-82. doi: 10.1016/j.molcel.2009.12.036.

Abstract

Innate immune responses are critical for the immediate protection against microbial infection. In Drosophila, infection leads to the rapid and robust production of antimicrobial peptides through two NF-kappaB signaling pathways-IMD and Toll. The IMD pathway is triggered by DAP-type peptidoglycan, common to most Gram-negative bacteria. Signaling downstream from the peptidoglycan receptors is thought to involve K63 ubiquitination and caspase-mediated cleavage, but the molecular mechanisms remain obscure. We now show that PGN stimulation causes caspase-mediated cleavage of the imd protein, exposing a highly conserved IAP-binding motif (IBM) at its neo-N terminus. A functional IBM is required for the association of cleaved IMD with the ubiquitin E3-ligase DIAP2. Through its association with DIAP2, IMD is rapidly conjugated with K63-linked polyubiquitin chains. These results mechanistically connect caspase-mediated cleavage and K63 ubiquitination in immune-induced NF-kappaB signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Motifs
  • Animals
  • Caspases / physiology*
  • Drosophila / enzymology*
  • Drosophila / metabolism
  • Drosophila Proteins / metabolism*
  • Drosophila Proteins / physiology
  • Inhibitor of Apoptosis Proteins / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • Models, Biological
  • Molecular Sequence Data
  • NF-kappa B / metabolism*
  • Sequence Alignment
  • Signal Transduction*
  • Ubiquitin-Protein Ligases
  • Ubiquitination

Substances

  • DIAP2 protein, Drosophila
  • Drosophila Proteins
  • Inhibitor of Apoptosis Proteins
  • NF-kappa B
  • imd protein, Drosophila
  • Ubiquitin-Protein Ligases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Caspases
  • dredd protein, Drosophila