bims-nucpor 2023-09-03 papers

Issue of 2023‒09‒03
four papers selected by
Sara Mingu, Johannes Gutenberg University

FEBS Lett. 2023 Aug 31.

You are who your friends are - nuclear pore proteins as components of chromatin-binding complexes.

Nuclear pore complexes (NPCs) are large multi-component protein complexes that are embedded in the nuclear envelope, where they mediate nucleocytoplasmic transport. In addition to supporting transport, nuclear pore components, termed nucleoporins (Nups), can interact with chromatin and influence genome function. A subset of Nups can also localize to the nuclear interior and bind chromatin intranuclearly, providing an opportunity to investigate chromatin-associated functions of Nups outside of the transport context. This review focuses on the gene regulatory functions of such intranuclear Nups, with a particular emphasis on their identity as components of several chromatin regulatory complexes. Recent proteomic screens have identified Nups as interacting partners of active and repressive epigenetic machinery, architectural proteins, and DNA replication complexes, providing insight into molecular mechanisms via which Nups regulate gene expression programs. This review summarizes these interactions and discusses their potential functions in the broader framework of nuclear genome organization.

Keywords: Nup; chromatin; gene expression; gene regulation; genome architecture; nuclear organization; nuclear pore complex; nucleoporin; transcription; transcriptional memory

DOI: https://doi.org/10.1002/1873-3468.14728

FEBS Lett. 2023 Sep 01.

Nuclear pore complex and nucleocytoplasmic transport disruption in neurodegeneration.

América Chandía Cristi, Sampath Rapuri, Alyssa N Coyne.

Nuclear pore complexes (NPCs) play a critical role in maintaining the equilibrium between the nucleus and cytoplasm, enabling bidirectional transport across the nuclear envelope, and are essential for proper nuclear organization and gene regulation. Perturbations in the regulatory mechanisms governing NPCs and nuclear envelope homeostasis have been implicated in the pathogenesis of several neurodegenerative diseases. The ESCRT-III pathway emerges as a critical player in the surveillance and preservation of well-assembled, functional NPCs, as well as nuclear envelope sealing. Recent studies have provided insights into the involvement of nuclear ESCRT-III in the selective reduction of specific nucleoporins associated with neurodegenerative pathologies. Thus, maintaining quality control of the nuclear envelope and NPCs represents a pivotal element in the pathological cascade leading to neurodegenerative diseases. This review describes the constituents of the nuclear-cytoplasmic transport machinery, encompassing the nuclear envelope, NPC, and ESCRT proteins, and how their structural and functional alterations contribute to the development of neurodegenerative diseases.

Keywords: ALS; ESCRT; FTD; neurodegeneration; nuclear pore complex; nucleocytoplasmic transport; nucleoporins

DOI: https://doi.org/10.1002/1873-3468.14729

STAR Protoc. 2023 Aug 30. pii: S2666-1667(23)00519-1. [Epub ahead of print]4(3): 102552

Protocol to image and quantify nuclear pore complexes using high-resolution laser scanning confocal microscopy.

Jocelyn D Mich-Basso, Bernhard Kühn.

Nuclear pore complexes are pathways for nuclear-cytoplasmic communication that participate in chromatin organization. Here, we present a protocol to image and quantify the number of nuclear pore complexes in cells. We describe steps for cell plating and culture, immunofluorescence detection, and confocal microscopy visualization of nuclear pore complexes. We then detail quantification and 3D data analysis. This protocol utilizes digital thresholding under human supervision for quantification of nuclear pore complexes. For complete details on the use and execution of this protocol, please refer to Han et al.1.

Keywords: Cell Biology; Microscopy

DOI: https://doi.org/10.1016/j.xpro.2023.102552

Brain. 2023 Aug 28. pii: awad291. [Epub ahead of print]

SUN1 facilitates CHMP7 nuclear influx and injury cascades in sporadic amyotrophic lateral sclerosis.

Victoria Baskerville, Sampath Rapuri, Emma Mehlhop, Alyssa N Coyne.

We have recently identified the aberrant nuclear accumulation of the ESCRT-III protein CHMP7 as an initiating event that leads to a significant injury to the nuclear pore complex (NPC) characterized by the reduction of specific nucleoporins (Nups) from the neuronal NPC in sporadic ALS (sALS) and C9orf72 ALS/FTD induced pluripotent stem cell (iPSC) derived neurons (iPSNs), a phenomenon also observed in postmortem patient tissues. Importantly, this NPC injury is sufficient to contribute to TDP-43 dysfunction and mislocalization, a common pathological hallmark of neurodegenerative diseases. However, the molecular mechanisms and events that give rise to increased nuclear translocation and/or retention of CHMP7 to initiate this pathophysiological cascade remain largely unknown. Here, using an iPSN model of sALS, we demonstrate that impaired NPC permeability barrier integrity and interactions with the LINC complex protein SUN1 facilitate CHMP7 nuclear localization and the subsequent "activation" of NPC injury cascades. Collectively, our data provide mechanistic insights in the pathophysiological underpinnings of ALS/FTD and highlight SUN1 as a potent contributor to and modifier of CHMP7 mediated toxicity in sALS pathogenesis.

Keywords: CHMP7; POM121; TDP-43; amyotrophic lateral sclerosis; nuclear pore complex

DOI: https://doi.org/10.1093/brain/awad291