WEHI Special Ubiquitin Signalling Seminar hosted by Professor David Komander

Dr Tom Snelling

MRC-PPU, University of Dundee, Scotland, UK

The role of ALPK1 in innate immune signalling and autoinflammatory disease

Davis Auditorium

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Including Q&A session

Alpha protein kinase 1 (ALPK1) is an atypical kinase that is activated allosterically by a bacterial metabolite called ADP-heptose, triggering an innate immune signalling pathway that leads to the production of inflammatory cytokines to combat bacterial infection. It is now clear that mutations in ALPK1 cause two human diseases. The ALPK1[V1092A] mutation accounts for around 35% of cases of spiradenocarcinoma tested, which are growths on the skin that are invariably fatal. In contrast the ALPK1[T237M] and ALPK1[Y254C] mutations cause ROSAH syndrome, an autosomal dominant genetic disease causing destruction of the retina and consequent blindness at a young age. We have found that these mutant forms of ALPK1 are activated not only by ADP-heptose, but also by human metabolites, representing the first examples of disease caused by the loss of specificity of a kinase for its allosteric activator. This raises the possibility of developing selective inhibitors of the mutant forms of ALPK1 by targeting the altered allosteric binding site. A further, unpublished mutation causing ROSAH syndrome has also been identified, which will be presented during this talk.

All Welcome!