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

Buchwalter, Abigail; Schulte, Roberta; Tsai, Hsiao; Capitanio, Juliana S.; Hetzer, Martin W.

doi:10.1101/695643

Cited by 6 publications

(15 citation statements)

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“…In an initial functional analysis, we examined Cgrrf1 and Rnf185 for a potential role in the proteosomal turnover of emerin and LBR, proteins that have half-lives of ∼1.5-3.5 days in myoblasts (Buchwalter et al, 2019). First, we analyzed the levels of endogenous emerin and LBR in MEFs that were stably transduced with the ectopic E3 ligases (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In these cases, the prey may be labeled by a peripheral ER pool of emerin-TbID or LBR-TbID that might be present at ER-organelle membrane contact sites (MCS). In addition, since emerin is known to traverse the secretory pathway en route to the plasma membrane and endosome (Buchwalter et al, 2019), labeling could occur in secretory pathway compartments downstream of the peripheral ER. Potential functions of these prey in relation to emerin and LBR, either at the NE, MCS, or other cellular locations, remain to be investigated.…”

Section: Discussionmentioning

confidence: 99%

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Shared and distinctive neighborhoods of emerin and LBR revealed by proximity labeling and quantitative proteomics

Cheng

Zhang

Abhinav

et al. 2022

Preprint

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Emerin and LBR are abundant transmembrane proteins of the nuclear envelope (NE) that are concentrated at the inner nuclear membrane (INM). Although both proteins interact with chromatin and nuclear lamins, they have distinctive biochemical and functional properties. Here we have deployed proximity labeling using the engineered biotin ligase TurboID (TbID) and quantitative proteomics to compare the neighborhoods of emerin and LBR in cultured mouse embryonic fibroblasts (MEFs). Our analysis revealed 232 high confidence proximity partners (HCPP) that interact selectively with emerin and/or LBR, 49 of which are shared by both. These included previously characterized NE-concentrated proteins, as well as a host of additional proteins not previously linked to emerin or LBR functions. Many of these are TM proteins of the ER and include two E3 ubiquitin ligases. Using the proximity ligation assay as an orthogonal approach, we validated the interactions described by proximity labeling for 11/12 proteins analyzed, supporting the robustness of our analysis. Overall, this work presents methodology that may be used for large-scale mapping of the landscape of the INM and reveals a group of new proteins with potential functional connections to emerin and LBR.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Shared and distinctive neighborhoods of emerin and LBR revealed by proximity labeling and quantitative proteomics

Cheng

Zhang

Abhinav

et al. 2022

Preprint

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“…Indeed, several indications link, directly or indirectly, laminopathies to an impairment of UPS [68][69][70] . Specific components of the UPS are activated by lamin miss-expression 68,71,72 and clearance of the inner nuclear membrane proteins have been reported to be proteasome-mediated 73,74 . Furthermore, some deleterious mutations of the lamin A-C proteins specifically affect their interaction with ubiquitin E3 ligases 62,72,75 .…”

Section: Discussionmentioning

confidence: 99%

Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness

Sferra

Fortugno

Motta

et al. 2021

Brain

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Leukodystrophies are a heterogeneous group of rare inherited disorders that involve preferentially the white matter of the central nervous system (CNS). These conditions are characterized by a primary glial cell and myelin sheath pathology of variable etiology, which causes secondary axonal degeneration, generally emerging with disease progression. Whole exome sequencing performed in 5 large consanguineous nuclear families allowed to identify homozygosity for two recurrent missense variants affecting highly conserved residues of RNF220 as the causative event underlying a novel form of leukodystrophy with ataxia and sensorineural deafness. We report on two homozygous missense variants (p.R363Q and p.R365Q) in the ubiquitin E3 ligase RNF220 as the cause underlying a novel form of leukodystrophy with ataxia and sensorineural deafness having fibrotic cardiomyopathy and hepatopathy as associated features, in seven consanguineous families. Mass spectrometry analysis identified lamin B1 as RNF220 binding protein and co-immunoprecipitation experiments demonstrated reduced binding of both RNF220 mutants to lamin B1. We demonstrate that RNF220 silencing in Drosophila melanogaster specifically affects proper localization of lamin Dm0, the fly lamin B1 orthologue, promotes its aggregation, and causes a neurodegenerative phenotype, strongly supporting the functional link between RNF220 and lamin B1. Finally, we demonstrate that RNF220 plays a crucial role in the maintenance of nuclear morphology: mutations primary skin fibroblasts determine nuclear abnormalities such as blebs, herniations and invaginations, which are typically observed in cells of patients affected by laminopathies. Overall, our data identify RNF220 as a gene implicated in leukodystrophy with ataxia and sensorineural deafness, and document a critical role of RNF220 in the regulation of nuclear lamina. Our findings provide further evidence on the direct link between nuclear lamina dysfunction and neurodegeneration.

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“…The detailed events underlying NE reformation were reviewed recently ( Ungricht and Kutay, 2017 ). Here we review mechanisms that maintain the NE proteome in interphase after the NE has formed, which is critical for cellular homeostasis since INM proteins that became effectively diluted due to cell duplication or are constantly removed via proteolysis (the average half-life of INM proteins is ∼3–4 d; Buchwalter et al. , 2019b ) need to be replaced.…”

Section: Protein Turnover At the Inm: An Enhancer Of Compartmental Idmentioning

confidence: 99%

“…, 2014 ) and higher ( Tsai et al. , 2016 ; Buchwalter et al. , 2019b ) eukaryotes, where it performs functions analogous to the ER-associated degradation (ERAD) machinery ( Smoyer and Jaspersen, 2019 ).…”

Section: Protein Turnover At the Inm: An Enhancer Of Compartmental Idmentioning

confidence: 99%

Lipid and protein dynamics that shape nuclear envelope identity

Bahmanyar

Schlieker

2020

MBoC

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The nuclear envelope (NE) is continuous with the endoplasmic reticulum (ER), yet the NE carries out many functions distinct from those of bulk ER. This functional specialization depends on a unique protein composition that defines NE identity and must be both established and actively maintained. The NE undergoes extensive remodeling in interphase and mitosis, so mechanisms that seal NE holes and protect its unique composition are critical for maintaining its functions. New evidence shows that closure of NE holes relies on regulated de novo lipid synthesis, providing a link between lipid metabolism and generating and maintaining NE identity. Here, we review regulation of the lipid bilayers of the NE and suggest ways to generate lipid asymmetry across the NE despite its direct continuity with the ER. We also discuss the elusive mechanism of membrane fusion during nuclear pore complex (NPC) biogenesis. We propose a model in which NPC biogenesis is carefully controlled to ensure that a permeability barrier has been established before membrane fusion, thereby avoiding a major threat to compartmentalization.

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

Cited by 6 publications

References 50 publications

Shared and distinctive neighborhoods of emerin and LBR revealed by proximity labeling and quantitative proteomics

Shared and distinctive neighborhoods of emerin and LBR revealed by proximity labeling and quantitative proteomics

Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness

Lipid and protein dynamics that shape nuclear envelope identity

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