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3. Lamin A/C phosphorylation at serine 22 is a conserved heat shock response to regulate nuclear adaptation during stress

Author

Virtanen, Laura, primary, Holm, Emilia, additional, Halme, Mona, additional, West, Gun, additional, Lindholm, Fanny, additional, Gullmets, Josef, additional, Irjala, Juho, additional, Heliö, Tiina, additional, Padzik, Artur, additional, Meinander, Annika, additional, Eriksson, John E., additional, and Taimen, Pekka, additional

Published
2023
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4. A heterozygous p.S143P mutation in LMNA associates with proteasome dysfunction and enhanced autophagy-mediated degradation of mutant lamins A and C

Author

West, Gun, Turunen, Minttu, Aalto, Anna, Virtanen, Laura, Li, Song-Ping, Heliö, Tiina, Meinander, Annika, Taimen, Pekka, HUS Heart and Lung Center, Clinicum, Department of Medicine, and Helsinki University Hospital Area

Subjects
autophagy, CARDIOMYOPATHY, STRESS, ubiquitin (Ub), UBIQUITIN, DISEASE, ubiquitin-proteasome degradation system, FUSION, QUALITY CONTROL, AGGRESOMES, lamin A/C (LMNA), 1182 Biochemistry, cell and molecular biology, disease mutations, INHIBITORS, SYSTEM, degradation, ACCUMULATION
Abstract

Lamins A and C are nuclear intermediate filament proteins that form a proteinaceous meshwork called lamina beneath the inner nuclear membrane. Mutations in the LMNA gene encoding lamins A and C cause a heterogenous group of inherited degenerative diseases known as laminopathies. Previous studies have revealed altered cell signaling pathways in lamin-mutant patient cells, but little is known about the fate of mutant lamins A and C within the cells. Here, we analyzed the turnover of lamins A and C in cells derived from a dilated cardiomyopathy patient with a heterozygous p.S143P mutation in LMNA. We found that transcriptional activation and mRNA levels of LMNA are increased in the primary patient fibroblasts, but the protein levels of lamins A and C remain equal in control and patient cells because of a meticulous interplay between autophagy and the ubiquitin-proteasome system (UPS). Both endogenous and ectopic expression of p.S143P lamins A and C cause significantly reduced activity of UPS and an accumulation of K48-ubiquitin chains in the nucleus. Furthermore, K48-ubiquitinated lamins A and C are degraded by compensatory enhanced autophagy, as shown by increased autophagosome formation and binding of lamins A and C to microtubule-associated protein 1A/1B-light chain 3. Finally, chaperone 4-PBA augmented protein degradation by restoring UPS activity as well as autophagy in the patient cells. In summary, our results suggest that the p.S143P-mutant lamins A and C have overloading and deleterious effects on protein degradation machinery and pharmacological interventions with compounds enhancing protein degradation may be beneficial for cell homeostasis.

Published
2022

6. Lamin A/C phosphorylation at serine 22 is a conserved heat shock response to regulate nuclear adaptation during stress

Author

Virtanen, Laura, primary, Holm, Emilia, additional, Halme, Mona, additional, West, Gun, additional, Lindholm, Fanny, additional, Gullmets, Josef, additional, Irjala, Juho, additional, Heliö, Tiina, additional, Padzik, Artur, additional, Meinander, Annika, additional, Eriksson, John E., additional, and Taimen, Pekka, additional

Published
2022
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12. Deleterious assembly of mutant p.S143P lamin A/C causes ER stress in familial dilated cardiomyopathy

Author

West, Gun, primary, Gullmets, Josef, additional, Virtanen, Laura, additional, Li, Song Ping, additional, Keinänen, Anni, additional, Shimi, Takeshi, additional, Mauermann, Monika, additional, Heliö, Tiina, additional, Kaartinen, Maija, additional, Ollila, Laura, additional, Kuusisto, Johanna, additional, Eriksson, John E., additional, Goldman, Robert D., additional, Herrmann, Harald, additional, and Taimen, Pekka, additional

Published
2016
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13. LMNAMutation c.917T>G (p.L306R) Leads to Deleterious Hyper-Assembly of Lamin A/C and Associates with Severe Right Ventricular Cardiomyopathy and Premature Aging

Author

Alastalo, Tero-Pekka, primary, West, Gun, additional, Li, Song-Ping, additional, Keinänen, Anni, additional, Helenius, Mikko, additional, Tyni, Tiina, additional, Lapatto, Risto, additional, Turanlahti, Maila, additional, Heikkilä, Päivi, additional, Kääriäinen, Helena, additional, Laakso, Markku, additional, Mauermann, Monika, additional, Herrmann, Harald, additional, Pihkala, Jaana, additional, and Taimen, Pekka, additional

Published
2015
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14. Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy.

Author

West, Gun, Gullmets, Josef, Virtanen, Laura, Song-Ping Li, Keinänen, Anni, Shimi, Takeshi, Mauermann, Monika, Heliö, Tiina, Kaartinen, Maija, Ollila, Laura, Kuusisto, Johanna, Eriksson, John E., Goldman, Robert D., Herrmann, Harald, and Taimen, Pekka

Subjects
*CARDIOMYOPATHIES, *DILATED cardiomyopathy, *IDIOPATHIC dilated cardiomyopathy, *HYPERTROPHIC cardiomyopathy, *MYOCARDITIS
Abstract

Mutation of the LMNA gene, encoding nuclear lamin A and lamin C (hereafter lamin A/C), is a common cause of familial dilated cardiomyopathy (DCM). Among Finnish DCM patients, the founder mutation c.427T>C (p.S143P) is the most frequently reported genetic variant. Here, we show that p.S143P lamin A/C is more nucleoplasmic and soluble than wild-type lamin A/C and accumulates into large intranuclear aggregates in a fraction of cultured patient fibroblasts as well as in cells ectopically expressing either FLAG- or GFP-tagged p.S143P lamin A. In fluorescence loss in photobleaching (FLIP) experiments, non-aggregated EGFP-tagged p.S143P lamin A was significantly more dynamic. In in vitro association studies, p.S143P lamin A failed to form appropriate filament structures but instead assembled into disorganized aggregates similar to those observed in patient cell nuclei. A whole-genome expression analysis revealed an elevated unfolded protein response (UPR) in cells expressing p.S143P lamin A/C. Additional endoplasmic reticulum (ER) stress induced by tunicamycin reduced the viability of cells expressing mutant lamin further. In summary, p.S143P lamin A/C affects normal lamina structure and influences the cellular stress response, homeostasis and viability. [ABSTRACT FROM AUTHOR]

Published
2016
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17. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide

Author

D’Angelo, Giovanni, primary, Polishchuk, Elena, additional, Tullio, Giuseppe Di, additional, Santoro, Michele, additional, Campli, Antonella Di, additional, Godi, Anna, additional, West, Gun, additional, Bielawski, Jacek, additional, Chuang, Chia-Chen, additional, van der Spoel, Aarnoud C., additional, Platt, Frances M., additional, Hannun, Yusuf A., additional, Polishchuk, Roman, additional, Mattjus, Peter, additional, and De Matteis, Maria Antonietta, additional

Published
2007
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21. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide

Author

Peter Mattjus, Roman S. Polishchuk, Gun West, Chia-Chen Chuang, Jacek Bielawski, Anna Godi, Antonella Di Campli, Aarnoud C. van der Spoel, Frances M. Platt, Elena Polishchuk, Maria Antonietta De Matteis, Giovanni D'Angelo, Yusuf A. Hannun, Giuseppe Di Tullio, Michele Santoro, D'Angelo, Giovanni, Polishchuk, Elena, Tullio, Giuseppe Di, Santoro, Michele, Campli, Antonella Di, Godi, Anna, West, Gun, Bielawski, Jacek, Chuang, Chia Chen, Van Der Spoel, Aarnoud C., Platt, Frances M., Hannun, Yusuf A., Polishchuk, Roman, Mattjus, Peter, and DE MATTEIS, Maria Antonietta

Subjects
Ceramides, Glucosylceramides, Models, Biological, Glycosphingolipids, Cell Line, Ceramide, symbols.namesake, chemistry.chemical_compound, Phosphatidylinositol Phosphates, Sphingosine, Animals, Humans, Phosphatidylinositol, Glycosphingolipid, Adaptor Proteins, Signal Transducing, Physics, Multidisciplinary, biology, Animal, Phosphatidylinositol Phosphate, Cell Membrane, Signal transducing adaptor protein, Biological Transport, Golgi apparatus, Cell biology, Pleckstrin homology domain, Structural biology, chemistry, Glycolipid transfer protein, symbols, biology.protein, Glucosylceramide, lipids (amino acids, peptides, and proteins), Signal transduction, Human, trans-Golgi Network
Abstract

The molecular machinery responsible for the generation of transport carriers moving from the Golgi complex to the plasma membrane relies on a tight interplay between proteins and lipids. Among the lipid-binding proteins of this machinery, we previously identified the four-phosphate adaptor protein FAPP2, the pleckstrin homology domain of which binds phosphatidylinositol 4-phosphate and the small GTPase ARF1. FAPP2 also possesses a glycolipid-transfer-protein homology domain. Here we show that human FAPP2 is a glucosylceramide-transfer protein that has a pivotal role in the synthesis of complex glycosphingolipids, key structural and signalling components of the plasma membrane. The requirement for FAPP2 makes the whole glycosphingolipid synthetic pathway sensitive to regulation by phosphatidylinositol 4-phosphate and ARF1. Thus, by coupling the synthesis of glycosphingolipids with their export to the cell surface, FAPP2 emerges as crucial in determining the lipid identity and composition of the plasma membrane.

Published
2007

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