Abstract
The integrity of the nuclear membranes coupled to the selective barrier of nuclear pore complexes (NPCs) are essential for the segregation of nucleoplasm and cytoplasm. Mechanical membrane disruption or perturbation to NPC assembly triggers an ESCRT-dependent surveillance system that seals nuclear pores: how these pores are sensed and sealed is ill defined. Using a budding yeast model, we show that the ESCRT Chm7 and the integral inner nuclear membrane (INM) protein Heh1 are spatially segregated by nuclear transport, with Chm7 being actively exported by Xpo1/Crm1. Thus, the exposure of the INM triggers surveillance with Heh1 locally activating Chm7. Sites of Chm7 hyperactivation show fenestrated sheets at the INM and potential membrane delivery at sites of nuclear envelope herniation. Our data suggest that perturbation to the nuclear envelope barrier would lead to local nuclear membrane remodeling to promote membrane sealing. Our findings have implications for disease mechanisms linked to NPC assembly and nuclear envelope integrity.
Highlights
The molecular machinery that biochemically segregates the nucleus and the cytoplasm has been extensively investigated
While there has been considerable focus over the last few decades on mechanisms that control the targeting of proteins and lipids to distinct intracellular compartments, it is important to understand the protective mechanisms that maintain this compartmentalization in the face of challenges to membrane integrity and/or the specific biochemical identity of organelles
This surveillance system appears to be set up to respond directly to perturbations in the nuclear envelope barrier in a way that we suggest is agnostic as to whether the perturbation is a result of defectively formed nuclear pore complexes (NPCs) or a mechanical disruption of the nuclear membranes
Summary
The molecular machinery that biochemically segregates the nucleus and the cytoplasm has been extensively investigated. There is an emerging body of work linking the function of NTRs and NPCs with neurodegenerative diseases like ALS and FTD (Nousiainen et al, 2008; Freibaum et al, 2015; Jovicicet al., 2015; Kaneb et al, 2015; Zhang et al, 2015; Kim and Taylor, 2017; Shi et al, 2017).
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