Dissecting Torsin/cofactor function at the nuclear envelope: a genetic study

Laudermilch, Ethan; Tsai, Pei-Ling; Graham, Morven; Turner, Elizabeth M.; Zhao, Chenguang; Schlieker, Christian

doi:10.1091/mbc.e16-07-0511

Cited by 80 publications

(160 citation statements)

References 57 publications

(101 reference statements)

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“…Interestingly, morphologically analogous herniations have also been observed in human[63], mouse[64–68], worm[69], and fly[60] cells upon disruption of the function of the ER-lumenal AAA+ ATPase Torsin A and its membrane-spanning co-factors LAP1 and LULL1[63]. Recent high resolution EM tomography studies of Torsin knockout HeLa cells further supports the conclusion that these herniations arise due to a disruption in NPC assembly, as their bases have NPC-like structures[63].…”

Section: Introductionmentioning

confidence: 53%

“…Recent high resolution EM tomography studies of Torsin knockout HeLa cells further supports the conclusion that these herniations arise due to a disruption in NPC assembly, as their bases have NPC-like structures[63]. In addition, similar to the yeast counterparts, the cytosolic-facing nup, Nup358, might not be properly assembled[71].…”

Section: Introductionmentioning

confidence: 99%

“…Further, Torsin A has been implicated in an egress pathway for so-called “Mega” RNPs that functions in the cells of Drosophila neuromuscular junctions[70,97] and in sea urchin embryos[98]. A key challenge, however, will be to distinguish if the NE herniations observed in these cells are functionally distinct from those linked with NPC biogenesis in mammalian cell culture[63]. Regardless, the concept that proteins/RNAs might exit the nucleus through a vesicular intermediate remains attractive and has been hypothesized to function as a clearance mechanism for nuclear aggregates[99].…”

Section: Introductionmentioning

confidence: 99%

“…Regardless, the concept that proteins/RNAs might exit the nucleus through a vesicular intermediate remains attractive and has been hypothesized to function as a clearance mechanism for nuclear aggregates[99]. While there is no direct evidence to yet support this idea, such a pathway could be used to remove defective NPC assembly intermediates from the INM[14,100]; interestingly, K48-linked ubiquitin can be found concentrated within the herniations of Torsin knockout cell lines[63](Figure 2B–D), but the identity of the ubiquitylated proteins remains unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, a key challenge for the future is to identify the molecular mechanisms driving specific nuclear membrane remodeling events that can lead to often remarkable morphological changes to the NE. The introduction of membrane-remodeling proteins[17,19] and ATP-utilizing machineries[14,63,116] to the NE is clearly a step in this direction, however, it might be that their local regulation is the most important factor for defining whether membrane remodeling is productive or not. Once these regulatory processes are understood, perhaps there is a chance to define how they might contribute to disease.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Fantastic nuclear envelope herniations and where to find them

Thaller

Lusk

2018

Biochemical Society Transactions

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Morphological abnormalities of the bounding membranes of the nucleus have long been associated with human diseases from cancer to premature aging to neurodegeneration. Studies over the past few decades support that there are both cell intrinsic and extrinsic factors (e.g. mechanical force) that can lead to nuclear envelope “herniations”, a broad catch-all term that reveals little about the underlying molecular mechanisms that contribute to these morphological defects. While there are many genetic perturbations that could ultimately change nuclear shape, here, we focus on a subset of nuclear envelope herniations that likely arise as a consequence of disrupting physiological nuclear membrane remodeling pathways required to maintain nuclear envelope homeostasis. For example, stalling of the interphase nuclear pore complex (NPC) biogenesis pathway and/or triggering of NPC quality control mechanisms can lead to herniations in budding yeast, which are remarkably similar to those observed in human disease models of early-onset dystonia. By also examining the provenance of nuclear envelope herniations associated with emerging nuclear autophagy and nuclear egress pathways, we will provide a framework to help understand the molecular pathways that contribute to nuclear deformation.

show abstract

Section: Introductionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Fantastic nuclear envelope herniations and where to find them

Thaller

Lusk

2018

Biochemical Society Transactions

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Mechanisms of nuclear pore complex assembly – two different ways of building one molecular machine

2017

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The nuclear pore complex (NPC) mediates all macromolecular transport across the nuclear envelope. In higher eukaryotes that have an open mitosis, NPCs assemble at two points in the cell cycle: during nuclear assembly in late mitosis and during nuclear growth in interphase. How the NPC, the largest nonpolymeric protein complex in eukaryotic cells, self‐assembles inside cells remained unclear. Recent studies have started to uncover the assembly process, and evidence has been accumulating that postmitotic and interphase NPC assembly use fundamentally different mechanisms; the duration, structural intermediates, and regulation by molecular players are different and different types of membrane deformation are involved. In this Review, we summarize the current understanding of these two modes of NPC assembly and discuss the structural and regulatory steps that might drive the assembly processes. We furthermore integrate understanding of NPC assembly with the mechanisms for rapid nuclear growth in embryos and, finally, speculate on the evolutionary origin of the NPC implied by the presence of two distinct assembly mechanisms.

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Coordinating nucleoporin condensation and nuclear pore complex assembly

Kuiper,

Prophet,

Schlieker

2023

FEBS Letters

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The nuclear pore complex (NPC) is among the most elaborate protein complexes in eukaryotes. While ribosomes and proteasomes are known to require dedicated assembly machinery, our understanding of NPC assembly is at a relatively early stage. Defects in NPC assembly or homeostasis are tied to movement disorders, including dystonia and amyotrophic lateral sclerosis (ALS), as well as aging, requiring a better understanding of these processes to enable therapeutic intervention. Here, we discuss recent progress in the understanding of NPC assembly and highlight how related defects in human disorders can shed light on NPC biogenesis. We propose that the condensation of phenylalanine‐glycine repeat nucleoporins needs to be carefully controlled during NPC assembly to prevent aberrant condensation, aggregation, or amyloid formation.

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Dissecting Torsin/cofactor function at the nuclear envelope: a genetic study

Cited by 80 publications

References 57 publications

Fantastic nuclear envelope herniations and where to find them

Fantastic nuclear envelope herniations and where to find them

Mechanisms of nuclear pore complex assembly – two different ways of building one molecular machine

Coordinating nucleoporin condensation and nuclear pore complex assembly

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