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The transcriptional co-activator function of the LIM-domain protein nTrip6

Eukaryotic gene transcription is tightly regulated, such that a specific transcriptional program is turned on only when required in an organ/tissue/cell specific manner. The set of genes that is turned on in response to an environmental cue is determined by the activation of a selective group of transcription factors. Once activated, transcription factors bind specifically to DNA response elements in the regulatory region of the target genes and thereby activate transcription. This activation is mediated by the recruitment of other proteins to the promoter, the so-called co-activators. These proteins are recruited as part of multi-protein complexes via a direct or indirect interaction with chromatin bound transcription factors, resulting in the activation of transcription. An emerging class of proteins involved in the regulation of transcription are bridging factors. These proteins do not harbour any known co-activator function or domain, but are recruited to the promoter via a direct interaction with transcription factors, and mediate an increase in transcriptional activity, presumably through the recruitment of other co-activators. Therefore they can be considered as co-activators. Proteins belonging to the class of LIM-domain proteins can function as co-activators via this mechanism. Our group could show that the nuclear isoform of the LIM-domain protein Trip6, nTrip6, is an important regulator of the transcription factors AP-1 and NF- K B. nTrip6 functions as a novel transcriptional co-activator for both transcription factors. Moreover, nTrip6 is essential for the repression of AP-1 and NF- K B by another transcription factor, the glucocorticoid receptor (GR). GR represses the transcription of AP-1 and NF- K B target genes without binding to DNA, but by being tethered to the promoter bound by AP-1 or NF- K B. nTrip6 is essential for this so-called trans-repression, by mediating the tethering of GR to the promoter. This negative crosstalk is reciprocal: AP-1 and NF- K B can trans-repress GR by a tethering mechanism. In this work I showed that nTrip6 act as a selective co-activator for a subset of AP-1 dimers. Moreover, the interaction of AP-1 dimers with nTrip6 determines the ability of GR to trans-repress these AP-1 dimers, since GR is tethered to the promoter via its interaction with nTrip6. Similarly, nTrip6 acts as a co-activator for GR, and mediates the tethering of AP-1 and NF- K B to promoter-bound GR, as a first step in the trans-repression of GR by AP-1 and NF- K B. The co-activator function of nTrip6 necessitates its dimerisation through two dimerisation domains in its N-terminus. This dimerisation enables the recruitment of other proteins, presumably co-activators, to the promoter. These properties of nTrip6 are most likely common to other LIM-domain proteins. The ability of transcription factors to interact with several LIM-domain proteins enables fine tuning of the transcriptional response, by the recruitment of different co-activator complexes, and by the possibility of repressing crosstalks with other transcription factors.