Direct PA-binding by Chm7 is required for nuclear envelope surveillance at herniations

Thaller, David J; Tong, Danqing; Marklew, Christopher J.; Borah, Sapan; Ciani, Barbara; Lusk, C. Patrick

doi:10.1101/2020.05.04.074880

Cited by 5 publications

(4 citation statements)

References 100 publications

(192 reference statements)

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“…One is that PA or DAG recruit fusion proteins to the emerging NPC, and this fails with too little or too broadly distributed lipid. Indeed, PA has been shown to recruit ESCRTs to poorly inserted NPC (Thaller et al, 2020)although we note that the almost complete absence of normal NPC in the dTorsin KO can only be explained by impaired biogenesis. Another possibility is that PA metabolism affects biophysical membrane properties beyond what is permissive for fusion.…”

Section: Discussionmentioning

confidence: 62%

The Torsin/ NEP1R1-CTDNEP1/ Lipin axis regulates nuclear envelope lipid metabolism for nuclear pore complex insertion

Jacquemyn

Foroozandeh

Vints

et al. 2020

Preprint

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AbstractTorsin ATPases of the endoplasmic reticulum (ER) and nuclear envelope (NE) lumen inhibit Lipin-mediated phosphatidate (PA) to diacylglycerol (DAG) conversion by an unknown mechanism. This excess PA metabolism is implicated in TOR1A/TorsinA diseases, but it is unclear whether it explains why Torsin concomitantly affects nuclear structure, lipid droplets (LD), organelle and cell growth. Here a fly miniscreen identified that Torsins affect these events via the NEP1R1-CTDNEP1 phosphatase complex. Further, Torsin homo-oligomerization rather than ATPase activity was key to function. NEP1R1-CTDNEP1 activates Lipin by dephosphorylation. We show that Torsin prevents CTDNEP1 from accumulating in the NE and excludes Lipin from the nucleus. Moreover, this repression of nuclear PA metabolism is required for interphase nuclear pore biogenesis. We conclude that Torsin is an upstream regulator of the NEP1R1-CTDNEP1/ Lipin pathway. This connects the ER/NE lumen with PA metabolism, and affects numerous cellular events including it has a previously unrecognized role in nuclear pore biogenesis.HighlightsNuclear envelope PA-DAG-TAG synthesis is independently regulated by Torsin and Torip/LAP1Torsin removes CTDNEP1 from the nuclear envelope and excludes Lipin from the nucleusExcess nuclear envelope NEP1R1-CTDNEP1/ Lipin activity impairs multiple aspects of NPC biogenesisNEP1R1-CTDNEP1/ Lipin inhibition prevents cellular defects associated with TOR1A and TOR1AIP1 / LAP1 disease

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Section: Discussionmentioning

confidence: 62%

The Torsin/ NEP1R1-CTDNEP1/ Lipin axis regulates nuclear envelope lipid metabolism for nuclear pore complex insertion

Jacquemyn

Foroozandeh

Vints

et al. 2020

Preprint

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“…Insect : LKB1 [ 181 ], TREK-1 [ 182 ]. Yeast : Pah1 [ 183 ], Opi1p [ 38 , 184 ], Spo20p [ 38 , 185 , 186 ], Sso1p [ 187 ], Sec18p [ 188 , 189 ], Ups1 [ 190 , 191 ], Chm7 [ 192 ]. Plant : ABI1 [ 193 ], PP2CA [ 194 ], TGD2 [ 195 , 196 ], TGD4 [ 197 ], AtPDK1 [ 198 ], MKK7/9 [ 199 ], SnRK2.4 [ 200 ], PID [ 201 ], AtSphK1 [ 202 ], RGS1 [ 203 ], PEPC [ 204 ], LHY [ 205 ], CCA1 [ 205 ], Werewolf [ 206 ], AHL4 [ 207 ], AKT2 [ 208 ], MAP65-1 [ 209 ], RbohD160 [ 210 ], 14-3-3 protein [ 211 ], MtDef4 [ 211 ], NsD7 [ 212 ], SNX [ 213 ].…”

Section: Figurementioning

confidence: 99%

New Era of Diacylglycerol Kinase, Phosphatidic Acid and Phosphatidic Acid-Binding Protein

Sakane

Hoshino

Murakami

2020

IJMS

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Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid (PA). Mammalian DGK consists of ten isozymes (α–κ) and governs a wide range of physiological and pathological events, including immune responses, neuronal networking, bipolar disorder, obsessive-compulsive disorder, fragile X syndrome, cancer, and type 2 diabetes. DG and PA comprise diverse molecular species that have different acyl chains at the sn-1 and sn-2 positions. Because the DGK activity is essential for phosphatidylinositol turnover, which exclusively produces 1-stearoyl-2-arachidonoyl-DG, it has been generally thought that all DGK isozymes utilize the DG species derived from the turnover. However, it was recently revealed that DGK isozymes, except for DGKε, phosphorylate diverse DG species, which are not derived from phosphatidylinositol turnover. In addition, various PA-binding proteins (PABPs), which have different selectivities for PA species, were recently found. These results suggest that DGK–PA–PABP axes can potentially construct a large and complex signaling network and play physiologically and pathologically important roles in addition to DGK-dependent attenuation of DG–DG-binding protein axes. For example, 1-stearoyl-2-docosahexaenoyl-PA produced by DGKδ interacts with and activates Praja-1, the E3 ubiquitin ligase acting on the serotonin transporter, which is a target of drugs for obsessive-compulsive and major depressive disorders, in the brain. This article reviews recent research progress on PA species produced by DGK isozymes, the selective binding of PABPs to PA species and a phosphatidylinositol turnover-independent DG supply pathway.

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“…When exposed to the inner nuclear membrane, Heh1 locally activates Chm7. This interaction is partly facilitated by the phosphatidic acid binding activity of Chm7 to the inner nuclear membrane [85]. After recruitment is established, Chm7 directly interacts with Heh2 to then recruit downstream factors that promote ESCRT-III assembly such as Snf7 and Vps4 [83] (Figure 2B).…”

Section: Alternative Splicing Regulates Escrt Recruitment To Npc Assembly Sitesmentioning

confidence: 99%

“…NPC recycling is also regulated through alternative splicing. Specifically, an unconventional ubiquitin-like protein known as Hub1 orchestrates a splicing event in the transcript of the Heh1 protein that in turn controls yeast Chm7 recruitment to the NPC [85,86]. Two splice isoforms for Heh1 are found in yeast, which encode a long (Heh1-L) and a short (Heh1-S) form of the Heh1 protein [87].…”

Section: Alternative Splicing Regulates Escrt Recruitment To Npc Assembly Sitesmentioning

confidence: 99%

Adding Some “Splice” to Stress Eating: Autophagy, ESCRT and Alternative Splicing Orchestrate the Cellular Stress Response

Habib

Cook

Mathavarajah

et al. 2021

Genes

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Autophagy is a widely studied self-renewal pathway that is essential for degrading damaged cellular organelles or recycling biomolecules to maintain cellular homeostasis, particularly under cellular stress. This pathway initiates with formation of an autophagosome, which is a double-membrane structure that envelopes cytosolic components and fuses with a lysosome to facilitate degradation of the contents. The endosomal sorting complexes required for transport (ESCRT) proteins play an integral role in controlling autophagosome fusion events and disruption to this machinery leads to autophagosome accumulation. Given the central role of autophagy in maintaining cellular health, it is unsurprising that dysfunction of this process is associated with many human maladies including cancer and neurodegenerative diseases. The cell can also rapidly respond to cellular stress through alternative pre-mRNA splicing that enables adaptive changes to the cell’s proteome in response to stress. Thus, alternative pre-mRNA splicing of genes that are involved in autophagy adds another layer of complexity to the cell’s stress response. Consequently, the dysregulation of alternative splicing of genes associated with autophagy and ESCRT may also precipitate disease states by either reducing the ability of the cell to respond to stress or triggering a maladaptive response that is pathogenic. In this review, we summarize the diverse roles of the ESCRT machinery and alternative splicing in regulating autophagy and how their dysfunction can have implications for human disease.

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Direct PA-binding by Chm7 is required for nuclear envelope surveillance at herniations

Cited by 5 publications

References 100 publications

The Torsin/ NEP1R1-CTDNEP1/ Lipin axis regulates nuclear envelope lipid metabolism for nuclear pore complex insertion

The Torsin/ NEP1R1-CTDNEP1/ Lipin axis regulates nuclear envelope lipid metabolism for nuclear pore complex insertion

New Era of Diacylglycerol Kinase, Phosphatidic Acid and Phosphatidic Acid-Binding Protein

Adding Some “Splice” to Stress Eating: Autophagy, ESCRT and Alternative Splicing Orchestrate the Cellular Stress Response

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