WEHI PhD Completion Seminar hosted by Professors James Vince and Seth Masters

Andreas Dumortier
PhD Student

Vince Laboratory – Immunity division, WEHI

Masters Laboratory – Hudston Institute of Medical Research

E3 ligase CRISPR screen uncovers a gate on the NLRP1 inflammasome in human skin

Davis Auditorium

Join via TEAMS

Including Q&A session

Inflammasome regulation is well described in circulating immune cells, which home to infection sites and elicit an inflammatory response; most notably NLRP3-dependent pyroptosis. Far less is known about the inflammasome-forming proteins of barrier epithelium, such as NLRP1. Keratinocytes, though fixed in a differentiation hierarchy, are capable of NLRP1 pyroptosis, raising the question of how pyroptotic cell death is regulated in such a rigid tissue context.

NLRP1 is activated by ribotoxic stress downstream of ZAKα, triggered by UV damage and other insults to the ribosome. Activation requires ubiquitination and proteasomal degradation of the NLRP1 N-terminal fragment, which releases the active C-terminus. To find the E3 ligases responsible, we used automated robotics to run an arrayed CRISPR screen in N/TERT keratinocytes: 646 ubiquitin ligase genes, two independent sgRNAs each, 1292 knockout populations imaged at high throughput. Our top hit unfolded into a curiosity-driven PhD project, in which a pathway that lets cells measure their own environment turned out to restrain the NLRP1 inflammasome.

Andreas is a Belgian clinician who practised at the Netherlands Cancer Institute (NKI-AVL) in Amsterdam before starting his PhD. Alongside his research, he co-founded Nucleate Australia, a not-for-profit supporting academic biotech spinouts.

All welcome!