The Inner Nuclear Membrane Is a Metabolically Active Territory that Generates Nuclear Lipid Droplets

Romanauska, Anete; Köhler, Alwin

doi:10.1016/j.cell.2018.05.047

Cited by 229 publications

(314 citation statements)

References 46 publications

(78 reference statements)

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“…Among differential lipids, other classes are also present. These include triacylglycerides, which could be explained by changes in the so-called lipid droplets, recently described in the nucleoplasm [37] where it may derive from inner nuclear membrane [38]. Since lipid droplet physiological role in nuclei is mainly unknown, we cannot infer its pathophysiological significance in our samples.…”

Section: Discussionmentioning

confidence: 94%

Nuclear lipidome is altered in amyotrophic lateral sclerosis: a preliminary study

Ramírez‐Núñez¹,

Jové²,

Torres³

et al. 2019

Preprint

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In this pilot study, we show that nuclei in spinal cord from ALS patients exhibit a differential lipidomic signature. Among the differential lipid species we could annotate 41 potential identities. These comprise membrane-bound lipids such as phosphatidylethanolamines -including plasmalogens-and phosphatidylcholines but also other lipid classes such as glycosphingolipids, diacylglycerols, and triacylglycerides (potentially present as nuclear lipid droplets). These results were orthogonally validated by showing loss of alkyldihydroxyacetonephosphate synthase (AGPS), a key peroxisomal enzyme in plasmalogen synthesis, both in ALS necropsy samples, in human motor neurons derived from iPSC from ALS patients and in hSOD-G93A transgenic mice. Further, diacylglycerol content changes were associated to ALS-linked variations in relatedenzymes, such as phospholipase C ßI (PLCßI), the source of nuclear diacylglycerol, and protein kinase CßII (PKCßII), whose function partially depends on nuclei concentration of diacylglycerol. These results point out for not only a role of nuclear membrane lipids but also to lipids present in the nucleoplasm, suggesting an undisclosed role for this part of the subcellular lipidome in ALS pathophysiology.

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Section: Discussionmentioning

confidence: 94%

Nuclear lipidome is altered in amyotrophic lateral sclerosis: a preliminary study

Ramírez‐Núñez¹,

Jové²,

Torres³

et al. 2019

Preprint

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“…Whether such membrane is derived from new synthesis or from the mobilization of existing stores remains to be explored. Of note, recent work supports that even the INM may be metabolically active and have the capacity to generate new lipid locally (Romanauska and Köhler, 2018). Further, close examination of samples reveals that the morphology of the INM extensions are both sheet-like and tubular in nature -it is not immediately obvious how such membrane connections could be established but they closely resemble the 'normal' continuities between the ONM and the broader ER network ; together these data suggest that ER-shaping proteins and lipid synthesis pathways might play an important role in contributing to nuclear envelope sealing -topics for the future.…”

Section: Discussionmentioning

confidence: 99%

An ESCRT-LEM domain inner nuclear membrane protein surveillance system is poised to directly monitor the integrity of the nuclear envelope barrier and nuclear transport system

Thaller

Allegretti²,

Borah

et al. 2019

Preprint

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The integrity of the nuclear envelope membranes coupled to the diffusion barrier and selective transport properties of nuclear pore complexes (NPCs) are a prerequisite for the robust segregation of nucleoplasm and cytoplasm. Recent work supports that mechanical membrane disruption or perturbation to NPC assembly can trigger an ESCRT-dependent surveillance system that seals nuclear envelope pores: how these pores are sensed and sealed remains to be fully defined. Here, we show that the principal components of the nuclear envelope surveillance system in yeast, which includes the ESCRT Chm7 and the integral inner nuclear membrane (INM) protein Heh1, are spatially segregated by the nuclear transport system. Specifically, at steady state Chm7 is actively restricted from the nucleus by Crm1/Xpo1. Consistent with the idea that it is the exposure of the INM that triggers surveillance, the expression of a transmembrane anchor and the winged helix domain of Heh1 is sufficient to recruit and activate Chm7 at a membrane interface. Correlative light electron tomography under conditions of Chm7 hyper-activation further show the formation of an elaborate network of fenestrated sheets at the INM and suggest ER-membrane delivery at sites of nuclear envelope herniation. Our data point to a model in which exposure of Chm7 to Heh1, driven by any perturbation in the nuclear envelope barrier would lead to local nuclear envelope remodeling to promote membrane sealing. Our findings have implications for disease mechanisms associated with defects in NPC assembly and nuclear envelope integrity.* *

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“…The INM is contiguous with the outer nuclear membrane and cytoplasmic ER (Ungricht and Kutay, 2017) and thus could receive lipids by lateral diffusion from the ER (van Meer et al, 2008). However, the INM in yeast (Romanauska and Kohler, 2018) and mammals (Aitchison et al, 2015;Csaki et al, 2013;Haider et al, 2018;Peterson et al, 2011) harbours lipid biosynthetic enzymes and regulatory proteins suggestive of compartmentalized nuclear lipid synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Analogous to the ER, the INM is the site for de novo biogenesis of nLDs in yeast (Romanauska and Kohler, 2018) whereas in hepatoma cells, nLDs are derived from luminal ER LDs that enter the nucleus after dissolution of the INM (Soltysik et al, 2019). PML expression, in particular the PML-II isoform, aids in nLD biogenesis at the INM by disrupting lamin-free regions of the INM to allow luminal LD release (Ohsaki et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Lipid-associated PML domains regulate CCTα, Lipin1 and lipid homeostasis

Lee

Salsman

Foster³

et al. 2020

Preprint

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Nuclear LDs (nLDs) originate at the inner nuclear membrane by a mechanism that involves the promyelocytic leukemia (PML) protein. Here we demonstrate that nLDs in oleate-treated U2OS cells are associated with Lipid-Associated PML (LAP) domains that differ from canonical PML nuclear bodies by the relative absence of SUMO1, SP100 and DAXX. nLDs were also enriched in CTP:phosphocholine cytidylyltransferase a (CCTa), the phosphatidic acid phosphatase Lipin1 and diacylglycerol (DAG). High resolution imaging revealed that LAP domains and CCTa occupy distinct polarized regions on nLDs, and that loss of LAP domains in PML knockout U2OS cells reduced the recruitment of CCTa onto nLDs by its amphipathic a-helical M-domain. The association of Lipin1 and DAG with nLDs was also LAP domain-dependent. The disruption of CCTa and Lipin1 localization on nLDs in PML knockout cells resulted in the inhibition of phosphatidylcholine and triacylglycerol synthesis indicating that LAP domains are a unique PML subdomain involved in nLD assembly and regulation of lipid metabolism.

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The Inner Nuclear Membrane Is a Metabolically Active Territory that Generates Nuclear Lipid Droplets

Cited by 229 publications

References 46 publications

Nuclear lipidome is altered in amyotrophic lateral sclerosis: a preliminary study

Nuclear lipidome is altered in amyotrophic lateral sclerosis: a preliminary study

An ESCRT-LEM domain inner nuclear membrane protein surveillance system is poised to directly monitor the integrity of the nuclear envelope barrier and nuclear transport system

Lipid-associated PML domains regulate CCTα, Lipin1 and lipid homeostasis

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