Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals

Fung, Ho Yee Joyce; Fu, Szu Chin; Chook, Yuh Min

doi:10.7554/elife.23961

Cited by 80 publications

(122 citation statements)

References 51 publications

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“…This suggested that subcellular localization of CHMP7 could be a key determinant to position CHMP4B foci. The CHMP7 Cterminal motif previously annotated as a MIM1 motif 2,21 closely resembles a type 1a highaffinity nuclear export signal (NES) 22 (Fig. 1c), suggesting a mechanism to exclude this 45kDa protein from the nucleus 23 .…”

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confidence: 89%

Unrestrained ESCRT-III drives chromosome fragmentation and micronuclear catastrophe

Vietri

Schultz

Bellanger

et al. 2019

Preprint

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The ESCRT-III membrane fission machinery 1,2 restores nuclear envelope integrity during mitotic exit 3,4 and interphase 5,6 . Whereas primary nuclei resealing takes minutes, micronuclear envelope ruptures appear irreversible and result in catastrophic collapse associated with chromosome fragmentation and rearrangements (chromothripsis), thought to be a major driving force in cancer development 7-10 . Despite its importance 11-13 , the mechanistic underpinnings of nuclear envelope sealing in primary nuclei and the defects observed in micronuclei remain largely unknown. Here we show that CHMP7, the nucleator of ESCRT-III filaments at the nuclear envelope 3,14 , and the inner nuclear membrane protein LEMD2 15 act as a compartmentalization sensor detecting the loss of nuclear integrity. In cells with intact nuclear envelope, CHMP7 is actively excluded from the nucleus to preclude its binding to LEMD2. Nuclear influx of CHMP7 results in stable association with LEMD2 at the inner nuclear membrane that licenses local polymerization of ESCRT-III. Tight control of nuclear CHMP7 levels is critical, as induction of nuclear CHMP7 mutants is sufficient to induce unrestrained growth of ESCRT-III foci at the nuclear envelope, causing dramatic membrane deformation, local DNA torsional stress, single-stranded DNA formation and fragmentation of the underlying chromosomes. At micronuclei, membrane rupture is not associated with repair despite timely recruitment of ESCRT-III. Instead, micronuclei inherently lack the capacity to restrict accumulation of CHMP7 and LEMD2. This drives unrestrained ESCRT-III recruitment, membrane deformation and DNA defects that strikingly resemble those at primary nuclei upon induction of nuclear CHMP7 mutants. Preventing ESCRT-III recruitment suppresses membrane deformation and DNA damage, without restoring nucleocytoplasmic compartmentalization. We propose that the ESCRT-III nuclear integrity surveillance machinery is a double-edged sword, as its exquisite sensitivity ensures rapid repair at primary nuclei while causing unrestrained polymerization at micronuclei, with catastrophic consequences for genome stability 16-18 .The formation of dynamic endosomal sorting complex required for transport (ESCRT)-III filaments competent for membrane fission is exquisitely sensitive to balanced levels of the factors that control these filaments 1,2,19 . This is exemplified by depletion of the essential subunit CHMP2A that results in persistent accumulation of CHMP4B, the main component of ESCRT-III filaments, at the reforming nuclear envelope (NE) without successful sealing 3 . We found

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confidence: 89%

Unrestrained ESCRT-III drives chromosome fragmentation and micronuclear catastrophe

Vietri

Schultz

Bellanger

et al. 2019

Preprint

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“…Hundreds of different amino acid sequences have been experimentally validated as bona-fide NESs that bind the receptor with different affinity, and may be exported with different efficiency [33,42,43] . This high variability can be explained by the recent finding that NESs with differ-ent backbone conformations can bind the receptor, and that not all export signals occupy the XPO1 NESbinding groove to the same extent [44] .…”

Section: Xpo1-mediated Protein Nuclear Export: Cargos Mechanisms Andmentioning

confidence: 99%

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Sendino¹,

Omaetxebarria²,

Rodríguez³

2018

CDR

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Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published. Figure 1. Receptor-mediated nucleocytoplasmic transport of proteins. A: Illustrative overview of the nuclear import of a cargo protein bearing a "classical" NLS mediated by the Importina/Importinb heterodimer (left) and the nuclear export of a cargo protein bearing a "leucine-rich" NES mediated by XPO1 (right); B: schematic depiction of the nuclear pore complex, illustrating its main structural features; C: examples of nucleocytoplasmic transport signals. The NLSs of SV40 large T antigen (monopartite) and nucleoplasmin (bipartite) are shown, with the basic residues that characterize "classical" NLSs highlighted in red. Below, the NES of PKI and a general consensus sequence of "leucine-rich" NESs are shown. The characteristic hydrophobic residues (represented by f in the consensus) are highlighted in colors and underlined. NLS: nuclear localization signal; NES: nuclear export signal Conception of the work, draft and revision of the work: Sendino M, Omaetxebarria MJ, Rodríguez JA

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“…We hypothesize that the Mto1 NES-M may be a natural high-affinity NES. In recent years, the NES “consensus” has evolved in concert with new experimental findings (Dong et al, 2009, Fung et al, 2015, Fung et al, 2017, Guttler et al, 2010, Monecke et al, 2009). In particular, relative to an original consensus involving four spaced hydrophobic residues (Kutay & Guttinger, 2005), several high-affinity NESs depend on a fifth hydrophobic residue, which may also be present in the Mto1 NES-M (Fig.…”

Section: Discussionmentioning

confidence: 99%

Exportin Crm1 is repurposed as a docking protein to generate microtubule organizing centers at the nuclear pore

Bao

Spanos

Kojidani

et al. 2017

Preprint

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Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals

Cited by 80 publications

References 51 publications

Unrestrained ESCRT-III drives chromosome fragmentation and micronuclear catastrophe

Unrestrained ESCRT-III drives chromosome fragmentation and micronuclear catastrophe

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Exportin Crm1 is repurposed as a docking protein to generate microtubule organizing centers at the nuclear pore

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