Proteasomes tether to two distinct sites at the nuclear pore complex

Albert, Sahradha; Schaffer, Miroslava; Beck, Florian; Mosalaganti, Shyamal; Asano, Shoh; Thomas, Henry F.; Plitzko, Jürgen M.; Beck, Martin; Baumeister, Wolfgang; Engel, Benjamin D.

doi:10.1073/pnas.1716305114

Cited by 134 publications

(113 citation statements)

References 63 publications

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“…2F, H). This 209 indicates that mature, INM-localized proteins can be degraded in a proteasome-210 there (Albert et al, 2017). This is also consistent with a recent report that an unstable 213 INM protein mutant accumulates within the nucleus of mammalian cells when the 214 proteasome is inhibited (Tsai et al, 2016).…”

supporting

confidence: 85%

Selective clearance of the inner nuclear membrane protein emerin by vesicular transport during ER stress

Buchwalter

Schulte

Tsai

et al. 2019

Preprint

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The inner nuclear membrane (INM) is a subdomain of the endoplasmic reticulum (ER) that is gated by the nuclear pore complex. It is unknown whether proteins of the INM and ER are degraded through shared or distinct pathways in mammalian cells. We applied dynamic proteomics to profile protein half-lives and report that INM and ER residents turn over at similar rates, indicating that the INM’s unique topology is not a barrier to turnover. Using a microscopy approach, we observed that the proteasome can degrade INM proteins in situ. However, we also uncovered evidence for selective, vesicular transport-mediated turnover of a single INM protein, emerin, that is potentiated by ER stress. Emerin is rapidly cleared from the INM by a mechanism that requires emerin’s LEM domain to mediate vesicular trafficking to lysosomes. This work demonstrates that the INM can be dynamically remodeled in response to environmental inputs.

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supporting

confidence: 85%

Selective clearance of the inner nuclear membrane protein emerin by vesicular transport during ER stress

Buchwalter

Schulte

Tsai

et al. 2019

Preprint

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“…C. reinhardtii cells are particularly well suited for in situ structural biology, enabling high-resolution imaging of cellular structures 17-21 . This model organism is therefore an excellent candidate to address the question of how well current models of NPC architecture are transferable across eukaryotic species.…”

Section: Resultsmentioning

confidence: 99%

In situ architecture of the algal nuclear pore complex

Mosalaganti

Kosiński

Albert

et al. 2017

Preprint

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Nuclear pore complexes (NPCs) span the nuclear envelope and mediate nucleocytoplasmic exchange. They are a hallmark of eukaryotes and are deeply rooted in the evolutionary origin of cellular compartmentalization. NPCs have an elaborate architecture that has been well studied in vertebrates. Whether this architecture is unique or varies significantly in other eukaryotic kingdoms remains unknown, predominantly due to missing in situ structural data. Here, we report the architecture of the algal NPC from the early branching eukaryote Chlamydomonas reinhardtii and compare it to the human NPC. We find that the inner ring of the Chlamydomonas NPC has an unexpectedly large diameter, and the outer rings exhibit an asymmetric oligomeric state that is unprecedented compared to all previously proposed models of NPC architecture. Our study provides evidence that the NPC is subject to substantial structural variation between species. The divergent and conserved features of NPC architecture provide insights into the evolution of the nucleocytoplasmic transport machinery.

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“…For example, NPCs play an important role in genome stability and organization [150]: they are used as sites of gene activation [151][152][153] [reviewed in [147]], for anchoring of eroded telomeres, ERCs [154], and repair of DNA double-strand breaks [155][156][157]. More speculative, changes in NPC number and architecture could also change local protein degradation by the NPC-localized proteasome [158,159] or local translation of NPC components [160]. We conclude that nuclear pores, the physical gatekeepers to the nuclear interior, may well represent an important gatekeeper in aging, and boosting its quality control may provide opportunities to increase resilience to aging and age-related diseases.…”

Section: Discussionmentioning

confidence: 99%

Poor old pores—The challenge of making and maintaining nuclear pore complexes in aging

2020

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The nuclear pore complex (NPC) is the sole gateway to the nuclear interior, and its function is essential to all eukaryotic life. Controlling the functionality of NPCs is a tremendous challenge for cells. Firstly, NPCs are large structures, and their complex assembly does occasionally go awry. Secondly, once assembled, some components of the NPC persist for an extremely long time and, as a result, are susceptible to accumulate damage. Lastly, a significant proportion of the NPC is composed of intrinsically disordered proteins that are prone to aggregation. In this review, we summarize how the quality of NPCs is guarded in young cells and discuss the current knowledge on the fate of NPCs during normal aging in different tissues and organisms. We discuss the extent to which current data supports a hypothesis that NPCs are poorly maintained during aging of nondividing cells, while in dividing cells the main challenge is related to the assembly of new NPCs. Our survey of current knowledge points toward NPC quality control as an important node in aging of both dividing and nondividing cells. Here, the loss of protein homeostasis during aging is central and the NPC appears to both be impacted by, and to drive, this process.

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Proteasomes tether to two distinct sites at the nuclear pore complex

Cited by 134 publications

References 63 publications

Selective clearance of the inner nuclear membrane protein emerin by vesicular transport during ER stress

Selective clearance of the inner nuclear membrane protein emerin by vesicular transport during ER stress

In situ architecture of the algal nuclear pore complex

Poor old pores—The challenge of making and maintaining nuclear pore complexes in aging

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