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Principles of Cell Signaling and Biological Consequences

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Student #4 response to Student #14

20 May 2005

Student 4 Student 4

The immune deficiency (Imd) pathway in Drosophila is responsible for immune responses to Gram negative bacteria. This paper demonstrates cross-talk between the two branches of the Imd pathway, the Jnk (Basket) and NFkB (Relish) pathways. The NFkB pathway had previously been shown to negatively downregulate the Jnk pathway in Drosophila (Park et al., 2004) as well as in mammals (Tang et al., 2001; De Smaele et al., 2001), but bidirectional cross-talk between these pathways had not been demonstrated, although it had been suspected.

Using microarrays, the authors found that by knockdown of Basket (using RNAi) upregulated Relish-dependent genes, and vice- versa. This was confirmed using real-time PCR. They found that activator protein 1 (AP1), a chief target of Basket activation, was responsible for the respressive activity of Basket for Relish- dependent genes. Using ChIP, they showed that AP1 is recruited to the promoter of a Relish-dependent gene, Attacin-A, and that it recruits the histone deacetylase HDAC1 to downregulate Relish- activated Attacin-A transcription. Several other Relish-dependent genes contain AP1 binding sites (and do not require Ap1 for activation), suggesting that AP1 may act as a transcriptional repressor on a number of promoters. Overall, this paper convincingly illustrates a mechanism for the Jnk pathway to downregulate the NFkB pathway by repressing the transcription of genes specific to that pathway. This cross-talk is thought to terminate signaling after an appropriate immune response, in order to protect cells from an excess of harmful immune modulating agents.

As the student states, the experiments in this paper are well thought out and logical. The authors first look at global changes in gene expression using microarrays, then confirm these results and dissect out the precise mechanisms of cross-talk using other techniques. I also agree that this paper demonstrates an unusual method of cross-talk. I think it is especially interesting that the cross-talk occurs at such a downstream point of the NFkB pathway, so that it ensures that the downregulation is highly selective to that pathway. On the whole, I agree that this paper does effectively illustrate the concept of functional cross-talk between signaling pathways.

References:

Park JM et al. 2004. Targeting of TAK1 by the NF-kB protein Relish regulates the JNK-mediated immune response in Drosophila. Genes Dev. 18: 584-594 [PubMed] [Full Text in Virtual Journal] [Online Journal]

Tang G et al. 2001. Inhibition of JNK activation through NF-kB target genes. Nature 414: 313-317 [PubMed] [Online Journal]

De Smaele E et al. 2001. Induction of gadd45b by NF-kB downregulates pro-apoptotic JNK signaling. Nature 414: 308-313 [PubMed] [Online Journal]

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