An ESCRT-LEM protein surveillance system is poised to directly monitor the nuclear envelope and nuclear transport system

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.

eLife digest

With the exception of bacteria, living cells contain most of their DNA inside a structure called the nucleus. The membranes of the nucleus form a protective wall around the DNA, while pores within this wall act as entry check-points, controlling what can and cannot get inside. Maintaining the structure of this wall is critical for cell survival. Problems can occur if the nuclear wall or its pores become disrupted, as in the case of cancer and neurodegenerative diseases. Thankfully cells have developed a protective surveillance system that can rapidly identify and repair any damage made to the nuclear wall. However, how this damage is found and what activates its repair is poorly understood.

Now, Thaller et al. have investigated two key proteins that they suspected were involved in the surveillance of the nuclear border in budding yeast: Chm7 and Heh1. Chm7 is part of a complex group of proteins that can cut and sculpt the shape of membranes, while Heh1 is normally embedded on the inside of the nucleus. Thaller et al. discovered that, when the nuclear wall is disrupted, Heh1 recruits Chm7 to the site of damage and activates it. Once activated Chm7 can repair the damage to the nuclear wall, by sealing over defective nuclear pores and closing gaps caused by breakages.

Thaller et al. showed that the transport system that normally moves molecules into and out of the nucleus also imports Heh1 and actively excludes Chm7, physically segregating them to opposite sides of the nuclear border. If the nuclear wall becomes damaged this leads to the local meeting of Heh1 and Chm7 at these sites. Heh1 will then activate the membrane shaping mechanisms of Chm7, rapidly repairing the nuclear border in response to the damage.

It is possible cell structures other than the nucleus use a similar surveillance system to protect their borders. Manipulating the border surveillance system of the nucleus could be used to treat the detrimental impacts of damage caused to the nuclear wall by disease.