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.

Poor old pores—The challenge of making and maintaining nuclear pore complexes in aging

“…Pioneering work from the Lusk laboratory has revealed the first data on how cells deal with defective NPC intermediates. Although it is early days, the data support the following model for sealing off defective NPCs and defective NPC intermediates: Their recognition is achieved through the loss of spatial separation between the NE-specific ESCRT adaptor, Chm7, and the INM protein Heh1 [83]. When Chm7 reaches the nucleus, it binds to Heh1/Heh2, which allows sealing off the defective NPC.…”

“…In baker's yeast, some of the proteins that assist and monitor the assembly of NPCs are identified, but their mechanism of action is only beginning to be understood. Key players thus far identified are the INM proteins Heh1 and Heh2, the NE‐specific endosomal sorting complexes required for transport (ESCRT)‐III adaptor Chm7, and the ESCRT‐III/Vps4 system (see Box 2) . Interference with this quality control mechanism results in the accumulation of misassembled NPCs .…”

“…The pronounced decrease in abundance of Sec13 and Dyn2 during chronological aging may not reflect changes at the NPC but rather reflect their roles cell division [61,62]. Vps4 system (see Box 2) [68,69,83]. Interference with this quality control mechanism results in the accumulation of misassembled NPCs [69].…”

“…(A) Summary of nuclear transport-related changes occurring in replicative aging baker's yeast cell, as measured in [2,11,13]: (a) The abundance of indicated FG-Nups and proteins assisting in NPC assembly declines with replicative aging, (b) aged cells more frequently have NE herniations, and (c) nucleocytoplasmic exchange is decreased in aged cells. (B) Schematic representation of NPC assembly and nuclear transport dynamics in young cells based on [68,69,83]. (C) Model: In aged cells, the decrease in the abundance of several proteins that assist in NPC assembly (indicated by faded cartoons) causes the accumulation of misassembled NPCs in aged mother cells.…”

Cdc42 GTPase regulates ESCRTs in nuclear envelope sealing and ER remodeling

“…Maintenance of the nuclear envelope is critical for compartmentalization of the activities of the nucleus away from those of the cytoplasm, and requires the proper function of several proteins including the ESCRT and LEM-family proteins (Gu et al, 2017;Olmos et al, 2016;Olmos et al, 2015;Thaller et al, 2019;Vietri et al, 2015;Webster et al, 2014;Webster et al, 2016). The ESCRTs are a family of membrane-deforming proteins that mediate reverse-topology scission of membranes (Schöneberg et al, 2016).…”