Small, fat-filled lipid droplets remain spherical as they indent a nucleus, dilute the lamina, and cause rupture

Abstract

AbstractThe nucleus in many cell types is a stiff organelle, and yet fat-filled lipid droplets (FD’s) in the cytoplasm can be seen to indent and displace the nucleus. FD’s are phase-separated liquids with a poorly understood interfacial tension γ that determines how FD’s interact with other organelles. Here, micron-sized FD’s remain spherical as they indent both the nucleus and peri-nuclear actomyosin, dilute Lamin-B1 locally independent of Lamin-A,C, and trigger rupture with locally persistent accumulation in the nucleus of cGAS, a cytosolic DNA sensor. FD-nucleus interactions initiate rapid mis-localization of the essential DNA repair factor KU80, and nuclear rupture associates with DNA damage and perturbed cell cycle. Similar results are evident in FD-laden cells after constricted 3D-migration, which is impeded by FD’s. Spherical shapes of small FD’s are consistent with a high γ that we measure for FD’s mechanically isolated from fresh adipose tissue as ∼40_mN/m – which is far higher than other liquid condensates, but typical of oils in water and sufficiently rigid to disrupt cell structures.