Chm7 and Heh1 collaborate to link nuclear pore complex quality control with nuclear envelope sealing

Abstract

The integrity of the nuclear envelope barrier relies on membrane remodeling by the ESCRTs, which seal nuclear envelope holes and contribute to the quality control of nuclear pore complexes (NPCs); whether these processes are mechanistically related remains poorly defined. Here, we show that the ESCRT-II/III chimera, Chm7, is recruited to a nuclear envelope subdomain that expands upon inhibition of NPC assembly and is required for the formation of the storage of improperly assembled NPCs (SINC) compartment. Recruitment to sites of NPC assembly is mediated by its ESCRT-II domain and the LAP2-emerin-MAN1 (LEM) family of integral inner nuclear membrane proteins, Heh1 and Heh2. We establish direct binding between Heh2 and the "open" forms of both Chm7 and the ESCRT-III, Snf7, and between Chm7 and Snf7. Interestingly, Chm7 is required for the viability of yeast strains where double membrane seals have been observed over defective NPCs; deletion of CHM7 in these strains leads to a loss of nuclear compartmentalization suggesting that the sealing of defective NPCs and nuclear envelope ruptures could proceed through similar mechanisms.

Dissecting Torsin/cofactor function at the nuclear envelope: a genetic study

“…For example, the blebs may represent either stalled NPC assembly intermediates or defective NPCs. This would be consistent with work in budding yeast, in which endosomal sorting complexes required for transport and the AAA+ ATPase Vps4 act in a quality control pathway that prevents NPC misassembly, perhaps through the removal of defective NPC assembly intermediates (Webster et al ., 2014, 2016; Webster and Lusk, 2016). Moreover, the concept that defective NPCs might be covered by membrane seals was suggested based on the presence of similar NE herniations in budding yeast strains lacking Nup116, a central channel nup (Wente and Blobel, 1993).…”

Structures, Functions, and Dynamics of ESCRT-III/Vps4 Membrane Remodeling and Fission Complexes

“…The nuclear membrane has two opposed bilayers, and holes that cross both membranes are therefore filled with cytoplasm and are topologically equivalent to ILV bud necks. Specialized ESCRT-III/Vps4 complexes can seal openings in the nuclear envelope that are produced by a series of processes, including reformation of the postmitotic nucleus (Gu et al 2017; Olmos et al 2015, 2016; Vietri et al 2015), damage due to shear stress (Denais et al 2016, Raab et al 2016), and removal of embedded complexes like the nuclear pore complex (Webster et al 2014, 2016) and the spindle pole body (Gu et al 2017). ESCRT-dependent wound repair of plasma membranes and endolysosomal membranes differs from nuclear membrane sealing because these membranes are single bilayers.…”

Fantastic nuclear envelope herniations and where to find them

“…Interestingly, the molecular fusogen that drives INM-ONM fusion has eluded genetic (or biochemical) identification. Identifying the fusion mechanism is a priority as it is becoming clear that some NE herniations likely arise due to defects in NPC biogenesis, and/or, surveillance mechanisms that seal off defective NPCs[14,15]. …”

“…This assertion is based on our work demonstrating the NE recruitment of the ESCRT component Chm7 (the yeast orthologue of CHMP7) by the integral INM protein Heh1 (the orthologue of human LEM2) under conditions in which NPC assembly is blocked[15]; Chm7 recruitment is most striking in nup116Δ and apq12Δ cells, strongly correlating NE herniations with Chm7 function. Moreover, the viability and the maintenance of nuclear-cytosolic compartmentalization of nup116Δ [15] and apq12Δ [83] cells requires CHM7 . A role for the ESCRT machinery in NPC quality control is attractive as they are well established to form spiraling polymers capable of stitching membranes together at multiple subcellular locations[84].…”