Final Forum: Student #14

10 May 2005

014 014

Downregulation of lipopolysaccharide response in Drosophila by negative crosstalk between the AP1 and NF-kappaB signaling modules.

Kim T, Yoon J, Cho H, Lee WB, Kim J, Song YH, Kim SN, Yoon JH, Kim-Ha J, Kim YJ. Nature Immunol. 2005 Feb;6(2):211-8. [PubMed] [Online Journal]

Drosophila has two pathways of innate immunity with which it recognizes bacterial pathogens: the Toll pathway, which is triggered by LPS, and the Imd pathway, which is triggered by bacterial peptidoglycan (PGN) and is the focus of this paper. Imd activates dTAK, which then signals to two different transcription factors. The first one is Relish (a Drosophila homolog of NFkB,) which is activated by the phosphorylation of IKK. The second is AP-1, which is activated via Basket (the Drosophila homolog of Jnk.) It has already been shown that NFkB activation can downregulate AP-1 activation under certain conditions. In this paper, the authors show that the opposite is also true: AP-1 can downregulate NFkB- activated gene transcription. They demonstrate that the transcription of the Relish-dependent gene Attacin A is downregulated by AP-1. The mechanism involves the AP-1 transcription factor interaction with the histone deacetylase HDAC1, and recruiting it to the gene’s Relish promoter. The experiments, which involve microarray analysis, siRNA and ChIPs, are well thought out and progress logically, although the figures are not always clearly labeled.

Crosstalk between pathways can serve several different functions, often acting as a molecular switch between two different cell states or a coincidence detector. In this case, crosstalk acts a negative modulator, with two related pathways inhibiting each other’s transcription factors after several hours of activity. Since uncontrolled pro-inflammatory signals in response to bacterial infection can lead to septic shock or autoimmune disease, it is crucial to have machinery for shutting off these signaling pathways. This paper is especially interesting because crosstalk usually involves protein modification such a ubiquitination or phosphorylation, whereas here it is accomplished by acetylation of histones and chromatin remodeling. This novel mechanism provides an elegant method of shutting off pro-inflammatory signaling while providing a sufficient time delay.