Membrane repair in health and disease
Reparasjon av cellens membraner er viktig for å forebygge celleskader som fører til sykdom, men foreløpig vet vi lite om de molekylære mekanismene som brukes til dette formålet. I dette prosjektet vil vi teste hypotesen om at såkalte ESCRT-proteiner utgjør et cellulært maskineri som reparerer hull i cellens membraner. Eukaryotic cells contain a plasma membrane that separates them from other cells and the extracellular environment but also extensive systems of endomembranes that constitute various organelles. When the plasma membrane or endomembranes are damaged, diseases occur. Examples include gastrointestinal symptoms caused by bacterial toxins that permeabilize the plasma membrane of intestinal cells, muscle diseases caused by genetic mutations in proteins responsible for plasma membrane repair, and laminopathies caused by genetic mutations in genes encoding nuclear envelope proteins. Repair of cellular membranes is therefore an important, albeit underrated, mechanism that contributes to our health. On the other hand, because cancer cells are highly dependent on efficient membrane repair, mechanisms that promote such repair are potential targets in cancer therapy. In a recent Nature paper we showed that components of the endosomal sorting complex required for transport (ESCRT) machinery mediate sealing of holes in the reforming nuclear envelope during mitotic exit. Together with previous findings that implicate the ESCRT machinery in plasma membrane repair, this suggests that the ESCRT machinery could be specialized for sealing small holes in cellular membranes. With this as working hypothesis, we will study the involvement of the ESCRT machinery in repairing damage-induced holes in two distinct membranes – the nuclear envelope and lysosomes. Our results will be used to explore the concept of using ESCRT components as potential diagnostic markers and therapeutic targets in cancer cells. The project started in September 2016 with the employment of postdoc Maja Radulovic, and she is currently setting up the cell-based experimental models for testing the working hypothesis.