ESCRT-III mediates budding across the inner nuclear membrane and regulates its integrity

Arii, Jun; Watanabe, Mizuki; Maeda, Fumio; Tokai‐Nishizumi, Noriko; Chihara, Takahiro; Miura, Masayuki; Maruzuru, Yuhei; Koyanagi, Naoto; Kato, Akihisa; Kawaguchi, Yasushi

doi:10.1038/s41467-018-05889-9

Cited by 88 publications

(117 citation statements)

References 68 publications

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“…Like Comt/NSF, Shrub/CHMP4B has conserved membrane fusion functions. CHMP4B is a major component of the ESCRT-III complex, which mediates membrane fusion in many processes, including cytokinesis (Carlton and Martin-Serrano, 2007; Morita et al, 2007), viral budding (Arii et al, 2018; Johnson et al, 2018), and plasma membrane repair (Jimenez et al, 2014). Recent work has shown that ESCRT-III also mediates membrane sealing during nuclear envelope reassembly (Vietri et al, 2015; Olmos et al, 2015) and nuclear envelope repair (Denais et al, 2016; Raab et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

ESCRT-III–mediated membrane fusion drives chromosome fragments through nuclear envelope channels

Warecki

Ling

Bast

et al. 2020

Journal of Cell Biology

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Mitotic cells must form a single nucleus during telophase or exclude part of their genome as damage-prone micronuclei. While research has detailed how micronuclei arise from cells entering anaphase with lagging chromosomes, cellular mechanisms allowing late-segregating chromosomes to rejoin daughter nuclei remain underexplored. Here, we find that late-segregating acentric chromosome fragments that rejoin daughter nuclei are associated with nuclear membrane but devoid of lamin and nuclear pore complexes in Drosophila melanogaster. We show that acentrics pass through membrane-, lamin-, and nuclear pore–based channels in the nuclear envelope that extend and retract as acentrics enter nuclei. Membrane encompassing the acentrics fuses with the nuclear membrane, facilitating integration of the acentrics into newly formed nuclei. Fusion, mediated by the membrane fusion protein Comt/NSF and ESCRT-III components Shrub/CHMP4B and CHMP2B, facilitates reintegration of acentrics into nuclei. These results suggest a previously unsuspected role for membrane fusion, similar to nuclear repair, in the formation of a single nucleus during mitotic exit and the maintenance of genomic integrity.

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Section: Discussionmentioning

confidence: 99%

ESCRT-III–mediated membrane fusion drives chromosome fragments through nuclear envelope channels

Warecki

Ling

Bast

et al. 2020

Journal of Cell Biology

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“…Additionally, the size of the necks at the base of the INM evaginations and nuclear envelope herniations is suggestive of the presence of a spiraling polymer analogous to those observed in vitro and in vivo (McCullough et al, 2018), supporting that these necks are likely stabilized by ESCRTs. Thus, while we acknowledge that such INM evaginations might not be a physiological event in the nuclear envelope sealing process, it remains tempting to speculate that they might be in the context of proposed mechanisms of nuclear egress be it Mega-RNPs (Speese et al, 2012;Jokhi et al, 2013), viruses (Lee et al, 2012(Lee et al, , 2016Arii et al, 2018), or in nucleophagy mechanisms (Roberts et al, 2003;Dou et al, 2015;Mochida et al, 2015;Mostofa et al, 2018) that so-far remain obscure but would require a membrane scission step. Interestingly, recent work suggests that herpes virus nuclear egress requires ESCRTs (Arii et al, 2018), including a role in controlling interesting INM extensions into the nucleus; such intranuclear membrane might also be relevant in cell types that have so-called "nucleoplasmic reticulum" .…”

Section: Discussionmentioning

confidence: 93%

An ESCRT-LEM domain inner nuclear membrane protein surveillance system is poised to directly monitor the integrity of the nuclear envelope barrier and nuclear transport system

Thaller

Allegretti²,

Borah

et al. 2019

Preprint

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The integrity of the nuclear envelope membranes coupled to the diffusion barrier and selective transport properties of nuclear pore complexes (NPCs) are a prerequisite for the robust segregation of nucleoplasm and cytoplasm. Recent work supports that mechanical membrane disruption or perturbation to NPC assembly can trigger an ESCRT-dependent surveillance system that seals nuclear envelope pores: how these pores are sensed and sealed remains to be fully defined. Here, we show that the principal components of the nuclear envelope surveillance system in yeast, which includes the ESCRT Chm7 and the integral inner nuclear membrane (INM) protein Heh1, are spatially segregated by the nuclear transport system. Specifically, at steady state Chm7 is actively restricted from the nucleus by Crm1/Xpo1. Consistent with the idea that it is the exposure of the INM that triggers surveillance, the expression of a transmembrane anchor and the winged helix domain of Heh1 is sufficient to recruit and activate Chm7 at a membrane interface. Correlative light electron tomography under conditions of Chm7 hyper-activation further show the formation of an elaborate network of fenestrated sheets at the INM and suggest ER-membrane delivery at sites of nuclear envelope herniation. Our data point to a model in which exposure of Chm7 to Heh1, driven by any perturbation in the nuclear envelope barrier would lead to local nuclear envelope remodeling to promote membrane sealing. Our findings have implications for disease mechanisms associated with defects in NPC assembly and nuclear envelope integrity.* *

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“…It is tempting to speculate that not only Torsin A and B, but also other Torsins might be involved in this process. Incomplete scission of primary HSV-1 virions from the INM was also reported after depletion of ESCRT-III proteins [24]. It might be speculated that recruitment of an AAA+ ATPase (Torsin/Vps4) might alleviate the scission process mediated by the NEC proteins.…”

Section: Discussionmentioning

confidence: 96%

“…Although the molecular mechanism underlying INM-ONM fusion remains incompletely understood, several cellular proteins have been implicated in this process including the multi-subunit endosomal sorting complex required for transport III (ESCRT-III) and the ATPase-associated with various cellular activities (AAA+) protein Vps4 (reviewed in Otsuka and Ellenberg [21]). Recent work suggests that ESCRT-III and Vps4 are also important for herpesvirus nuclear egress [24][25][26], but conflicting findings have been reported [27,28].Two other potential cellular mediators of INM-ONM fusion during interphase NPC insertion are Torsin A (TorA) and TorB. As similar to Vps4, Torsins belong to the AAA+ ATPase superfamily.…”

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confidence: 99%

Function of Torsin AAA+ ATPases in Pseudorabies Virus Nuclear Egress

Hölper

Klupp

Luxton

et al. 2020

Cells

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Newly assembled herpesvirus nucleocapsids traverse the intact nuclear envelope by a vesicle-mediated nucleo-cytoplasmic transport for final virion maturation in the cytoplasm. For this, they bud at the inner nuclear membrane resulting in primary enveloped particles in the perinuclear space (PNS) followed by fusion of the primary envelope with the outer nuclear membrane (ONM). While the conserved viral nuclear egress complex orchestrates the first steps, effectors of fusion of the primary virion envelope with the ONM are still mostly enigmatic but might include cellular proteins like SUN2 or ESCRT-III components. Here, we analyzed the influence of the only known AAA+ ATPases located in the endoplasmic reticulum and the PNS, the Torsins (Tor), on nuclear egress of the alphaherpesvirus pseudorabies virus. For this overexpression of wild type and mutant proteins as well as CRISPR/Cas9 genome editing was applied. Neither single overexpression nor gene knockout (KO) of TorA or TorB had a significant impact. However, TorA/B double KO cells showed decreased viral titers at early time points of infection and an accumulation of primary virions in the PNS pointing to a delay in capsid release during nuclear egress.Cells 2020, 9, 738 2 of 19 genome at early stages of infection. Traffic into and out of the nucleus is thought to occur exclusively through NPCs (reviewed in Adam [3], Knockenhauer and Schwartz [4]). Interestingly, herpesvirus nucleocapsids are translocated through the nuclear envelope (NE) by a vesicle-mediated process designated as nuclear egress (reviewed in [5][6][7]).Budding of herpesvirus nucleocapsids at the INM is driven by the nuclear egress complex (NEC) composed of two conserved herpesviral proteins designated as pUL31 and pUL34 in the alphaherpesviruses pseudorabies virus (PrV) and herpes simplex viruses (HSV-1, -2) [5][6][7]. The NEC is not only required for efficient nuclear egress, thereby generating primary enveloped virions in the PNS, but also sufficient for vesicle formation and scission from artificial lipid membranes and the INM, [8][9][10][11]. In a subsequent step, this primary envelope fuses with the ONM to release the nucleocapsids into the cytoplasm (reviewed in [12]).Budding of nucleocapsids at the INM is quite well understood at the molecular level, while the fusion process of the primary envelope with the ONM remains mostly enigmatic. In contrast to reports for HSV-1 [13], the viral fusion machinery which is active during entry of herpesviruses is not involved in nuclear egress of PrV [14]. In addition, a variety of different PrV gene deletion mutants studied so far showed no detectable effect on nuclear egress arguing against a virus-encoded fusion machinery active at the NE. Only mutants lacking the alphaherpesvirus specific protein kinase pUS3 showed an impairment of nuclear translocation. In the absence of pUS3 [15][16][17] or by impairment of its kinase function [18][19][20] primary enveloped virions accumulate in herniations of the INM. However, pUS3 is not essential for viral re...

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ESCRT-III mediates budding across the inner nuclear membrane and regulates its integrity

Cited by 88 publications

References 68 publications

ESCRT-III–mediated membrane fusion drives chromosome fragments through nuclear envelope channels

ESCRT-III–mediated membrane fusion drives chromosome fragments through nuclear envelope channels

An ESCRT-LEM domain inner nuclear membrane protein surveillance system is poised to directly monitor the integrity of the nuclear envelope barrier and nuclear transport system

Function of Torsin AAA+ ATPases in Pseudorabies Virus Nuclear Egress

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