Toll receptor-mediated <em>Drosophila</em> immune response requires Dif, an NF-κB factor

Abstract

Multicellular organisms share a common burden of defending themselves against the invasion of microorganisms. Recent molecular genetic studies in plants, insects, and mammals reveal conserved pathways that signal host cells of microbial infection and elicit production of protective molecules (Ip et al. 1993; Whitham et al. 1994; Barillas-Mury et al. 1996; Medzhitov et al. 1997; Ryals et al. 1997; Han et al. 1998; Ip and Davis 1998; Yang et al. 1998). In tobacco, the N gene product mediates the resistance to tobacco mosaic virus. The N protein has homology to the intracellular domains of the Drosophila Toll and the mammalian interleukin-1 receptor (IL-1R) (Whitham et al. 1994). Such homology is also observed in the Arabidopsis RPP5 protein, which confers resistance to downy mildew pathogen (Parker et al. 1997). Using the Drosophila Toll sequence, various groups have further identified in human five novel Toll-like receptors (Medzhitov et al. 1997; Rock et al. 1998; Yang et al. 1998). These novel molecules probably represent true homologs of Toll by virtue of having homology in both intracellular and extracellular domains. At least some of these human Toll-like receptors can mediate aspects of immune response (Medzhitov et al. 1997; Rock et al. 1998; Yang et al. 1998). Therefore, the results support the idea that Toll-mediated signaling represents an ancient self-defense pathway. It has also been shown that the stress-activated JNK and p38 MAP kinase pathways, as well as the JAK–STAT pathway, may have similar functions in Drosophila (Han et al. 1998; Ip and Davis 1998; Liu et al. 1998; Mathey-Prevot and Perrimon 1998). Taken together, at least some of the pathways that mediate self-defense response in very diverse species are highly conserved.

The activation of Toll and IL-1R both lead to the mobilization of NF-κB factors, which have been shown to be present in many cell types to regulate genes that are involved in self-protection processes (Verma et al. 1995; Baeuerle and Baltimore 1996). In Drosophila, the first member of the NF-κB family, Dorsal, was identified in a screen for genes required for embryonic development. Dorsal is a key regulator in determining dorsoventral polarity (Drier and Steward 1997). Both Dorsal and NF-κB can bind to similar DNA sequences and have similar gene regulatory functions. Their activities are also modulated by highly conserved signaling pathways (Verma et al. 1995; Baeuerle and Baltimore 1996; Drier and Steward 1997; Wu and Anderson 1997). Despite the striking similarity of the molecular components involved, the biological processes (dorsoventral development vs. immune response) controlled by Dorsal and NF-κB pathways seemed rather disparate. This disparity, however, was reconciled by the implication of NF-κB-like molecules in regulating Drosophila antimicrobial response (Sun and Faye 1992; Engstrom et al. 1993; Ip et al. 1993; Kappler et al. 1993).

Insects battle microbial infection by synthesizing a spectrum of antimicrobial peptides that synergistically lyse invading microorganisms. Whereas >10 different antimicrobial peptides have been identified in different insects, approximately seven genes that encode such peptides have been cloned from Drosophila (Hoffmann et al. 1996; Hultmark 1993). Molecular analyses showed that the induction of these peptides in Drosophila probably involves NF-κB factors, which include Dif and Relish in addition to Dorsal (Ip et al. 1993; Lemaitre et al. 1995a; Petersen et al. 1995; Dushay et al. 1996; Gross et al. 1996). Therefore, previous reports suggest that the Toll–NF-κB signaling pathway represents an evolutionarily conserved cassette utilized in diverse species in the self-defense process. However, the implication of the insect NF-κB factors in immunity has been based on biochemical and molecular experiments. The understanding of how these molecules may function individually and in combination in whole animal requires further analysis. In this report we present genetic evidence demonstrating that Dif is an essential factor for some aspects of insect immunity.

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