Yeast Signalling Networks
ABOUT
Our research focuses on the interplay between bioactive lipids and cell signalling pathways in the homeostatic regulation of organelles and metabolism, and its role in aging and neurodegenerative disorders. We use genetic, biochemical and lipidomic approaches to identify new targets of this intricate signalling network and provide novel mechanistic insights into aging-associated cell attrition.
RESEARCH
We showed that the TORC1 effectors Sit4 and Sch9 proteins act as ceramide sensors and promote vacuolar and mitochondrial dysfunctions and premature aging. We identified hexokinase 2 and Atp2 as Sit4 targets in regulating cell cycle, mitochondria and lifespan. Importantly, Atp2 phosphoregulation stimulates G2/M phase transition. In turn, mitochondrial respiration bolsters Cdc28/Cdk1 stability, while mitochondrial remodelling has been linked to APC/C-Cdh1 activity, critical components of the cell cycle machinery.
In a yeast model of Niemann-Pick type C1, a lysosomal storage disorder, the Pkh1-Sch9 pathway and Sit4 are activated by sphingolipids and contribute to mitochondrial dysfunction and reduced lifespan. Furthermore, we proposed that changes in vesicle trafficking and iron accumulation contribute to reduced autophagy, expanding our grasp of the molecular mechanisms of the disease.
We also established a humanized yeast model of N88S seipinopathy, a motor neuron disease, and showed that N88S–N88S homo-oligomerization enhances mutant seipin toxicity associated with inclusion body formation, ER stress and oxidative damage. We also showed that TORC1 and PKA and cytosolic pH collectively regulate lipid droplet formation by targeting the vacuolar ATPase.
Collaborators: Yusuf Hannun (Stony Brook Univ., NY, USA), Francesc Posas (Universitat Pompeu Fabra, Barcelona, Spain), Chung-Yu Lan (National Tsing Hua University, Hsinchu, Taiwan), William A. Prinz (NIH, Bethesda, USA), Vineet Choudhary (AIIMS, New Delhi, India) and Manuela Côrte-Real (Univ. of Minho).
Team
Selected Publications
The ceramide activated protein phosphatase Sit4 impairs sphingolipid dynamics, mitochondrial function and lifespan in a yeast model of Niemann-Pick type C1. Biochimica et Biophysica Acta - Molecular Basis of Disease1864(1):79-88, 2018. [Journal: Article] [CI: 10] [IF: 4,3]
DOI: 10.1016/j.bbadis.2017.10.010 SCOPUS: 85031804747
Martins T.S., Pereira C., Canadell D., Vilaça R., Teixeira V., Moradas-Ferreira P., de Nadal E., Posas F., Costa V.,
The Hog1p kinase regulates Aft1p transcription factor to control iron accumulation. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids1863(1):61-70, 2018. [Journal: Article] [CI: 16] [IF: 4,4]
DOI: 10.1016/j.bbalip.2017.10.001 SCOPUS: 85032229876
Teixeira V., Medeiros T.C., Vilaça R., Ferreira J., Moradas-Ferreira P., Costa V.,
Ceramide signaling targets the PP2A-like protein phosphatase Sit4p to impair vacuolar function, vesicular trafficking and autophagy in Isc1p deficient cells. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids1861(1):21-33, 2016. [Journal: Article] [CI: 15] [IF: 5,5]
DOI: 10.1016/j.bbalip.2015.10.004 SCOPUS: 84944937082
Teixeira V., Costa V.,
Unraveling the role of the Target of Rapamycin signaling in sphingolipid metabolism. Progress in Lipid Research61:109-133, 2016. [Journal: Review] [CI: 34] [IF: 10,6]
DOI: 10.1016/j.plipres.2015.11.001 SCOPUS: 84952328556
Pereira C., Costa V., Martins L.M., Saraiva L.,
A yeast model of the Parkinson's disease-associated protein Parkin. Experimental Cell Research333(1):73-79, 2015. [Journal: Article] [CI: 23] [IF: 3,4]
DOI: 10.1016/j.yexcr.2015.02.018 SCOPUS: 84926408656
Vilaça R., Silva E., Nadais A., Teixeira V., Matmati N., Gaifem J., Hannun Y.A., Sá Miranda M.C., Costa V.,
Sphingolipid signalling mediates mitochondrial dysfunctions and reduced chronological lifespan in the yeast model of Niemann-Pick type C1. Molecular Microbiology91(3):438-451, 2014. [Journal: Article] [CI: 28] [IF: 4,4]
DOI: 10.1111/mmi.12470 SCOPUS: 84908101723
Barbosa A.D., Osório H., Sims K.J., Almeida T., Alves M., Bielawski J., Amorim M.A., Moradas-Ferreira P., Hannun Y.A., Costa V.,
Role for Sit4p-dependent mitochondrial dysfunction in mediating the shortened chronological lifespan and oxidative stress sensitivity of Isc1p-deficient cells. Molecular Microbiology81(2):515-527, 2011. [Journal: Article] [CI: 44] [IF: 5]
DOI: 10.1111/j.1365-2958.2011.07714.x SCOPUS: 79960193275
Mesquita A., Weinberger M., Silva A., Sampaio-Marques B., Almeida B., Leão C., Costa V., Rodrigues F., Burhans W.C., Ludovico P.,
Caloric restriction or catalase inactivation extends yeast chronological lifespan by inducing H2O2 and superoxide dismutase activity. Proceedings of the National Academy of Sciences of the United States of America107(34):15123-15128, 2010. [Journal: Article] [CI: 223] [IF: 9,8]
DOI: 10.1073/pnas.1004432107 SCOPUS: 77956987110
Almeida T., Marques M., Mojzita D., Amorim M.A., Silva R.D., Almeida B., Rodrigues P., Ludovico P., Hohmann S., Moradas-Ferreira P., Côrte-Real M., Costa V.,
Isc1p plays a key role in hydrogen peroxide resistance and chronological lifespan through modulation of iron levels and apoptosis. Molecular Biology of the Cell19(3):865-876, 2008. [Journal: Article] [CI: 81] [IF: 5,6]
DOI: 10.1091/mbc.E07-06-0604 SCOPUS: 41649101223
Costa V.M.V., Amorim M.A., Quintanilha A., Moradas-Ferreira P.,
Hydrogen peroxide-induced carbonylation of key metabolic enzymes in Saccharomyces cerevisiae: The involvement of the oxidative stress response regulators Yap1 and Skn7. Free Radical Biology and Medicine33(11):1507-1515, 2002. [Journal: Article] [CI: 129] [IF: 5,5]
DOI: 10.1016/S0891-5849(02)01086-9 SCOPUS: 0036890134