VPS4B orchestrates response to nuclear envelope stress by regulating ESCRT-III dynamics in glioblastoma

Abstract

The Nuclear envelope (NE) is frequently challenged by mechanical stimuli involving cells passing through a tight space and such stress is known as “NE stress.” Various factors that cooperate to repair the NE have been identified, including endosomal sorting complex required for transport-III (ESCRT-III). Recently, vacuolar protein sorting 4 homolog B (VPS4B) has been reported to modulate the recycling of ESCRT-III during NE repair, but the regulatory mechanism remains unclear. Our previous study revealed that U251MG cells, derived from the glioblastoma (GBM), exhibited nuclear deformation followed by DNA damage upon mechanical NE stress while these phenotypes were not observed in U87MG, another GBM-derived cell line. Here, we found that VPS4B expression was lower in U251MG than in U87MG. Our functional analysis demonstrated that insufficient VPS4B triggers an inadequate response to NE stress and that VPS4B regulates the dynamics of ESCRT-III, uncovering the mechanism underlying the NE stress response in GBM.