Mechanics of nuclear membranes

Abstract

Cellular nuclei are bound by two uniformly separated lipid membranes that are fused with each other at numerous donut-shaped pores. These membranes are structurally supported by an array of distinct proteins with distinct mechanical functions. As a result, the nuclear envelope possesses unique mechanical properties, which enables it to resist cytoskeletal forces. Here, we review studies that are beginning to provide quantitative insights into nuclear membrane mechanics. We discuss how the mechanical properties of the fused nuclear membranes mediate their response to mechanical forces exerted on the nucleus and how structural reinforcement by different nuclear proteins protects the nuclear membranes against rupture. We also highlight some open questions in nuclear envelope mechanics, and discuss their relevance in the context of health and disease.

Keywords: LINC complex; Membrane mechanics; Nuclear envelope.

Fig. 1.

Diversity of nuclear membrane shapes. (A) Nuclear membranes are continuous with the ER membranes. (B) The inset shows the ONM fused with the INM in a donut-like geometry at the nuclear pore. (C) The inset shows the NR; here, either the INM alone or both the INM and ONM can bend inwards. (D) The nuclear membrane can bleb, ultimately resulting in membrane rupture.

Fig. 2.

Schematic illustration of the nuclear envelope components that bear mechanical loads. (A) ONM nesprins bind to INM SUN protein trimers (Sosa et al., 2012), creating a mechanical linkage between the ONM and the INM; ONM nesprins link to the cytoskeleton, while INM proteins like SUN and emerin link the INM to the nuclear lamina. (B) Diagram depicting the possible forces on the ONM and INM. Tensile and shear forces from the cytoskeleton can act on the ONM, and forces from the lamina and/or chromatin can act on the INM. These forces are resisted in part by the inwardly directed forces in the LINC complex proteins. As the membrane passes through the NPC, the NPC can apply forces on the membrane to prevent an expansion of the NPC radius. Chromatin can apply either pushing or pulling forces onto the INM based on its compaction state. In addition, differences in the hydrostatic pressure between the nucleoplasm and the perinuclear space act on the INM, and the pressure difference between the perinuclear space and the cytoplasm acts on the ONM. Note, that some of these forces could act in opposite directions to those depicted here, depending on the direction of the external forces on the nucleus.

Fig. 3.

Lipid composition impacts bilayer bending. (A) A lipid molecule can have three types of geometries – inverted cone, cylindrical or cone. (B) Depending on which leaflet is enriched in the cone-shaped lipid in a bilayer, the bilayer will bend into different directions.

Fig. 4.

Possible modes of hole formation mechanisms in ruptured nuclei. (A) The ONM and INM may each have a hole after rupture (two-hole model). At the edge of these holes, lipids will undergo extreme bending (over a distance of 4–5 nm) to avoid exposure of hydrophobic tails to the aqueous medium (shown on the right). Such deformation costs energy, which manifests in the form of a line tension and opposes further expansion of the hole. (B) Alternatively, in the one-hole model, the ONM and INM can fuse with each other after rupture to form a donut-shaped single hole (shown on the right). A donut-shaped hole has no edge and hence has no line tension energy; therefore it allows for larger hole sizes of 40–50 nm, consistent with experimental observations. The gray arrows indicate the net outward pressure acting on the membrane, and the thick blue line indicates the nuclear lamina.