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Review
. 2024 Dec;15(1):2349085.
doi: 10.1080/19491034.2024.2349085. Epub 2024 May 3.

Nuclear and degradative functions of the ESCRT-III pathway: implications for neurodegenerative disease

Olivia Keeley  1   2 , Alyssa N Coyne  1   2
Affiliations
Review

Nuclear and degradative functions of the ESCRT-III pathway: implications for neurodegenerative disease

Olivia Keeley et al. Nucleus. 2024 Dec.

Abstract

The ESCRT machinery plays a pivotal role in membrane-remodeling events across multiple cellular processes including nuclear envelope repair and reformation, nuclear pore complex surveillance, endolysosomal trafficking, and neuronal pruning. Alterations in ESCRT-III functionality have been associated with neurodegenerative diseases including Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), and Alzheimer's Disease (AD). In addition, mutations in specific ESCRT-III proteins have been identified in FTD/ALS. Thus, understanding how disruptions in the fundamental functions of this pathway and its individual protein components in the human central nervous system (CNS) may offer valuable insights into mechanisms underlying neurodegenerative disease pathogenesis and identification of potential therapeutic targets. In this review, we discuss ESCRT components, dynamics, and functions, with a focus on the ESCRT-III pathway. In addition, we explore the implications of altered ESCRT-III function for neurodegeneration with a primary emphasis on nuclear surveillance and endolysosomal trafficking within the CNS.

Keywords: Amyotrophic lateral sclerosis; ESCRT-III pathway; endolysosomal trafficking; frontotemporal dementia; neurodegenerative diseases; nuclear pore complex; nuclear surveillance; protein degradation.

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Conflict of interest statement

ANC has submitted patents on methods and drugs to modulate various ESCRT-III proteins in neurodegeneration.

Figures

Figure 1.
Figure 1.
Overview of a subset ESCRT-III mediated cellular processes. A subset of known cellular processes that involved ESCRT-III membrane remodeling functions depicted in neurons.
Figure 2.
Figure 2.
ESCRT-III functions at the nuclear envelope and NPC. (a) Nuclear envelope sealing: upon nuclear envelope rupture, barrier to autoregulation factor (BAF) is recruited to ‘plug’ larger holes prior to sealing. For smaller ruptures, CHMP7 localizes to the nuclear periphery where it is exposed to the inner nuclear membrane protein LEMD2. Protein – protein interactions between CHMP7 and LEMD2 facilitate activation of CHMP7 and subsequent recruitment and polymerization of ESCRT-III subunits to seal nuclear envelope holes. VPS4 recruitment mediates ESCRT-III polymer disassembly and subunit reuse. (b) NPC surveillance and quality control: upon NPC misassembly within the nuclear envelope, CHMP7 localizes to the nuclear periphery where it is positioned to interact with LEMD2. CHMP7 is activated through physical association with LEMD2. ESCRT-III subunits are recruited to generate and stabilize membrane buds. Polymerization of ESCRT-III subunits and recruitment of VPS4 facilitates scission of membrane buds containing NPCs for degradation. VPS4 mediates ESCRT-III polymer disassembly and subunit exchange for reuse.
Figure 3.
Figure 3.
ESCRT-III mediated physiologic maintenance and pathologic disruption of NPCs in human neurons. (a) In normal human neurons, turnover of individual nucleoporin proteins to maintain NPC integrity and function is initiated by passive diffusion of CHMP7 to the nuclear space. CHMP7 is activated via currently undefined but LEMD2 independent protein – protein interactions. Activation of CHMP7 likely facilitates the recruitment and polymerization of ESCRT-III subunits. Individual nucleoporin proteins are removed from the NPC and degraded in a VPS4 dependent manner. VPS4 likely facilitates ESCRT-III polymer disassembly and subunit exchange and reuse. Exportin-1 (XPO1) actively exports CHMP7 from the nucleus, resulting in its ‘inactivation’ and maintaining low nuclear levels of CHMP7 under basal cellular conditions. Nucleoporins are synthesized and reinserted into the NPC. (b) In ALS neurons, the integrity of the passive diffusion permeability barrier is disrupted in a SUN1 dependent manner leading to a pathologic increase in the nuclear influx of CHMP7. CHMP7 is activated via currently undefined by LEMD2 independent protein – protein interactions. Activation of CHMP7 likely facilitates the recruitment and polymerization of ESCRT-III subunits. Individual nucleoporin proteins are removed from the NPC and degraded in a VPS4 dependent manner. VPS4 likely facilitates ESCRT-III polymer disassembly and subunit exchange and reuse. We hypothesize impaired interactions between CHMP7 and XPO1 or other Exportins abrogate its active nuclear export and facilitate nuclear accumulation of CHMP7 observed in ALS/FTD. In addition, we hypothesize that pathologic removal and degradation of nucleoporins is sustained via 1. sustained excessive nuclear influx of CHMP7 and/or 2. sustained LEMD2 independent activation of CHMP7 (e/g/persistent nuclear protein – protein interactions and/or 3. sustained VPS4 mediated nucleoporin removal from NPCs and/or 4. impaired nucleoporin reincorporation perhaps as a result of altered nuclear transport receptor and active nuclear import function. Collectively, sustained ‘overactivation’ of ESCRT-III mediated nucleoporin turnover gives rise to NPC disruptions in ALS/FTD human neurons.
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References

    1. Hatano T, Palani S, Papatziamou D, et al. Asgard archaea shed light on the evolutionary origins of the eukaryotic ubiquitin-ESCRT machinery. Nat Commun. 2022;13(1):3398. doi: 10.1038/s41467-022-30656-2 - DOI - PMC - PubMed
    1. Hurley JH. The ESCRT complexes. Crit Rev Biochem Mol Biol. 2010;45(6):463–20. doi: 10.3109/10409238.2010.502516 - DOI - PMC - PubMed
    1. Hurley JH. Escrts are everywhere. Embo J. 2015;34(19):2398–2407. doi: 10.15252/embj.201592484 - DOI - PMC - PubMed
    1. McCullough J, Frost A, Sundquist WI. Structures, functions, and dynamics of ESCRT-III/Vps4 membrane remodeling and fission complexes. Annu Rev Cell Dev Biol. 2018;34(1):85–109. doi: 10.1146/annurev-cellbio-100616-060600 - DOI - PMC - PubMed
    1. Olmos Y. The ESCRT machinery: remodeling, repairing, and sealing membranes. Membranes. 2022;12(6):633. doi: 10.3390/membranes12060633 - DOI - PMC - PubMed

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