A Membrane Sensing Mechanism Couples Local Lipid Metabolism to Protein Degradation at the Inner Nuclear Membrane

Lee, Shoken; Merta, Holly; Rodríguez, Jake W. Carrasquillo; Bahmanyar, Shirin

doi:10.2139/ssrn.4162077

Cited by 5 publications

(10 citation statements)

References 91 publications

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“…Since phosphatidylserine is a cylindrical-shaped lipid that favours the formation of flat membranes (Peeters et al, 2022), ER–NE junctions with highly-curved membranes may exclude phosphatidylserine and prevent its diffusion into the ONM. As NE lipid composition affects NE protein stability (Lee et al, 2023), ER–NE junctions may thus play a key role in NE lipid/protein homeostasis, as proposed previously (Bahmanyar & Schlieker, 2020). The average width of ER–NE junctions of 7–20 nm is larger than the diameter of most proteins (∼5 nm), but small enough to restrict the diffusion of large multimeric complexes and protein aggregates between the lumens of the ER and NE.…”

Section: Discussionmentioning

confidence: 68%

“…Since phosphatidylserine is a cylindrical-shaped lipid that favours the formation of flat membranes (Peeters et al, 2022), ER-NE junctions with highly-curved membranes may limit phosphatidylserine diffusion. As NE lipid composition affects NE protein stability (Lee et al, 2022), ER-NE junctions may function as selective lipid sorter and play a key role in NE protein homeostasis as proposed previously (Bahmanyar & Schlieker, 2020).…”

Section: Discussionmentioning

confidence: 84%

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The endoplasmic reticulum connects to the nucleus by constricted junctions that mature after open mitosis in mammalian cells

Bragulat-Teixidor¹,

Ishihara²,

Szucs³

et al. 2023

Preprint

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The endoplasmic reticulum (ER) is physically connected to the cell nucleus via junctions with the nuclear envelope (NE). These ER-NE junctions are essential for supplying the NE with lipids and transmembrane proteins that are synthesized in the ER. Despite the important role of ER-NE junctions, their biogenesis, architecture and maintenance across the cell cycle has remained elusive. In this study, by combining live cell imaging with quantitative three-dimensional electron microscopy, we systematically elucidated the ultrastructure of ER-NE junctions in mammalian cells. We discovered that ER-NE junctions exhibit a constricted hourglass shape that is different from the junctions within the ER. When ER-NE junctions are newly built during NE assembly at mitotic exit, their morphology resembles ER-ER junctions, but they become constricted starting in telophase. Altogether, our findings imply novel mechanisms that remodel ER-NE junctions and have functional implications for the lipid and protein traffic that are crucial for nuclear function.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 84%

The endoplasmic reticulum connects to the nucleus by constricted junctions that mature after open mitosis in mammalian cells

Bragulat-Teixidor¹,

Ishihara²,

Szucs³

et al. 2023

Preprint

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show abstract

“…In particular, CTDNEP1 was recently implicated in coordinating membrane biogenesis with cell division and loss of CTDNEP1 results in excess membrane production which affect chromosome dynamics ( Merta et al, 2021 ). A role for SUN2 in lipid metabolism was also recently proposed ( Lee et al, 2022 ), suggesting that the convoluted nuclei observed in cells expressing non-degradable SUN2 may result from excessive production of NE membranes. Thus, future studies should explore further how the function of CTDNEP1 in controlling SUN2 levels relates to its role in lipid regulation.…”

Section: Discussionmentioning

confidence: 77%

Regulated degradation of the inner nuclear membrane protein SUN2 maintains nuclear envelope architecture and function

Krshnan

Siu

Weijer

et al. 2022

eLife

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Nuclear architecture and functions depend on dynamic interactions between nuclear components (such as chromatin) and inner nuclear membrane (INM) proteins. Mutations in INM proteins interfering with these interactions result in disease. However, mechanisms controlling the levels and turnover of INM proteins remain unknown. Here, we describe a mechanism of regulated degradation of the INM SUN domain-containing protein 2 (SUN2). We show that Casein Kinase II and the C-terminal domain Nuclear Envelope Phosphatase 1 (CTDNEP1) have opposing effects on SUN2 levels by regulating SUN2 binding to the ubiquitin ligase Skp/Cullin1/F-BoxβTrCP (SCFβTrCP). Upon binding to phosphorylated SUN2, SCFβTrCP promotes its ubiquitination. Ubiquitinated SUN2 is membrane extracted by the AAA ATPase p97 and delivered to the proteasome for degradation. Importantly, accumulation of non-degradable SUN2 results in aberrant nuclear architecture, vulnerability to DNA damage and increased lagging chromosomes in mitosis. These findings uncover a central role of proteolysis in INM protein homeostasis.

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“…However, numerous studies have identified mechanoresponsive post‐transcriptional control over SUN2 levels, suggesting a role for regulated protein degradation pathway. Interestingly, insight into the possible mechanisms at play came from other experimental angles: the study of integral INM protein turnover [41] and crosstalk between lipid composition at the INM and the nuclear envelope proteome [42] (Fig. 3).…”

Section: Regulation Of Sun2 Levels Through Transcriptional Regulation...mentioning

confidence: 99%

“…New models for the regulation of SUN2 turnover. (1) When SUN2 (perhaps as a monomer or trimer) engages the INM with its amphipathic helix (AH, orange) in its nucleoplasmic domain (which may prefer regions with membrane packing defects [42]), it is stabilized. (2) Loss of engagement of the AH may permit phosphorylation of nearby ‘site 2’ (and possibly ‘site 1’) by casein kinase II (CK‐II), which is antagonized by the phosphatase CTDNEP1 [41].…”

Section: Regulation Of Sun2 Levels Through Transcriptional Regulation...mentioning

confidence: 99%

Dynamic regulation of LINC complex composition and function across tissues and contexts

King

2023

FEBS Letters

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The concept of mechanotransduction to the nucleus through a direct force transmission mechanism has fascinated cell biologists for decades. Central to such a mechanism is the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which spans the nuclear envelope to couple the cytoplasmic cytoskeleton to the nuclear lamina. In reality, there is not one LINC complex identity, but instead a family of protein configurations of varied composition that exert both shared and unique functions. Regulated expression of LINC complex components, splice variants, and mechanoresponsive protein turnover mechanisms together shape the complement of LINC complex forms present in a given cell type. Disrupting specific gene(s) encoding LINC complex components therefore gives rise to a range of organismal defects. Moreover, evidence suggests that the mechanical environment remodels LINC complexes, providing a feedback mechanism by which cellular context influences the integration of the nucleus into the cytoskeleton. In particular, evidence for crosstalk between the nuclear and cytoplasmic intermediate filament networks communicated through the LINC complex represents an emerging theme in this active area of ongoing investigation.

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A Membrane Sensing Mechanism Couples Local Lipid Metabolism to Protein Degradation at the Inner Nuclear Membrane

Cited by 5 publications

References 91 publications

The endoplasmic reticulum connects to the nucleus by constricted junctions that mature after open mitosis in mammalian cells

The endoplasmic reticulum connects to the nucleus by constricted junctions that mature after open mitosis in mammalian cells

Regulated degradation of the inner nuclear membrane protein SUN2 maintains nuclear envelope architecture and function

Dynamic regulation of LINC complex composition and function across tissues and contexts

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