Lipid and protein dynamics that shape nuclear envelope identity

Abstract

The nuclear envelope (NE) is continuous with the endoplasmic reticulum (ER), yet the NE carries out many functions distinct from those of bulk ER. This functional specialization depends on a unique protein composition that defines NE identity and must be both established and actively maintained. The NE undergoes extensive remodeling in interphase and mitosis, so mechanisms that seal NE holes and protect its unique composition are critical for maintaining its functions. New evidence shows that closure of NE holes relies on regulated de novo lipid synthesis, providing a link between lipid metabolism and generating and maintaining NE identity. Here, we review regulation of the lipid bilayers of the NE and suggest ways to generate lipid asymmetry across the NE despite its direct continuity with the ER. We also discuss the elusive mechanism of membrane fusion during nuclear pore complex (NPC) biogenesis. We propose a model in which NPC biogenesis is carefully controlled to ensure that a permeability barrier has been established before membrane fusion, thereby avoiding a major threat to compartmentalization.

FIGURE 1:

Features of the nuclear envelope and ER and regulation of and functions for lipid asymmetry at the inner nuclear membrane (INM). (A) Schematic of the continuous NE and ER membranes. The inner nuclear membrane (INM) facing the nucleoplasm and outer nuclear membrane (ONM) physically linked to the ER at NE-ER junctions are separated by a lumen designated perinuclear space (PNS). A nuclear pore complex (NPC) is located at a fusion point between the INM/ONM to generate the pore membrane. Highlighted in different shades of red are proteins that may regulate lipid trafficking between the NE and ER as well as enzymes and proteins that are regulated by or sense bilayer lipid composition (PKC and Nup133), or that regulate de novo lipid synthesis (CTDNEP1/lipin and CCTα). The curvature of the membrane bilayers may also play a role in restricting diffusion of lipid species past NE-ER junctions (negative curvature) or the pore membrane (positive curvature). Schematic of a membrane fusion reaction (middle) highlights membrane bending at each intermediate step. (B) The de novo glycerolipid synthesis pathway. Mol% for lipid species specific to ER/NE membranes is shown (van Meer et al., 2008).

FIGURE 2:

A fusion checkpoint for nuclear pore biogenesis. Nuclear pore assembly after nuclear envelope reformation proceeds through an inside-out protrusion mechanism starting from the nuclear side. Early assembly intermediates contain NPC constituents that deform the inner nuclear membrane (INM). This structure needs to expand to bring the INM and outer nuclear membrane (ONM) in close proximity for fusion. Either the integrity of the NPC assembly intermediate is sensed or the transport competence of a late assembly intermediate is required to initiate fusion. This hypothetical checkpoint mechanism would prevent a transient perturbation of NE integrity and can potentially explain why multiple, distinct NPC assembly defects lead to NE blebs resembling late assembly intermediates that got arrested before fusion (see the text).