TRANSCRIPTIONALNLRS · NLRs AS TRANSCRIPTIONAL REGULATORS

MHC molecules are central to our immune system and are therefore also involved in several pathologies. MHCII transcription is controlled by proximal promoter sequences, which are cooperatively bound by several factors forming the ‘MHC enhanceosome’. Upon recruitment to this complex, the NLR family member CIITA promotes MHCII transcription.We recently found that our mice deficient for the NLR NLRC5 exhibit markedly reduced MHCI expression in lymphocytes. Importantly, endogenous NLRC5 occupies H-2 proximal promoter regions and drives gene transcription.We now plan to characterize novel NLR-mediated transcriptional regulatory pathways controlling MHC expression. We will investigate the enhanceosome and the transcriptional regulators interacting with NLRC5 as well as the role of NLRC5 in gene expression more broadly. We will also address the function of NLRC3, which is homologous to CIITA and NLRC5, by using novel conditional knockout mice. Our preliminary data indicate that conventional Nlrc3-KO mice show embryonic lethality and that NLRC3 can localize to the nucleus, supporting the hypothesis that it acts as an essential transcriptional regulator. We will therefore investigate NLRC3 function in immunity and reproduction, paying particular attention to the regulation of non-classical MHCI molecules known to play a role in embryogenesis. Interestingly, we identified RFX7, which is homologous to the enhanceosome component RFX5, as an interactor of NLRC3. Although RFX7 has been associated with leukemia development, this factor remains functionally uncharacterized, and we plan to study its role by generating knockout mice.Novel aspects of MHC transcriptional regulation are emerging, highlighting a combinatorial system wherein NLRs play a more general role than realized so far. A better understanding of the mechanisms regulating MHC transcription is fundamental to design novel therapeutic approaches relevant to immune disorders, malignancies, and infertility.