Cofilin/Twinstar phosphorylation levels increase in response to impaired coenzyme a metabolism.
Coenzyme A (CoA) is a pantothenic acid-derived metabolite essential for many fundamental cellular processes including energy, lipid and amino acid metabolism. Pantothenate kinase (PANK), which catalyses the first step in the conversion of pantothenic acid to CoA, has been associated with a rare neurodegenerative disorder PKAN. However, the consequences of impaired PANK activity are poorly understood. Here we use Drosophila and human neuronal cell cultures to show how PANK deficiency leads to abnormalities in F-actin organization. Cells with reduced PANK activity are characterized by abnormally high levels of phosphorylated cofilin, a conserved actin filament severing protein. The increased levels of phospho-cofilin coincide with morphological changes of PANK-deficient Drosophila S2 cells and human neuronal SHSY-5Y cells. The latter exhibit also markedly reduced ability to form neurites in culture--a process that is strongly dependent on actin remodeling. Our results reveal a novel and conserved link between a metabolic biosynthesis pathway, and regulation of cellular actin dynamics.
Department of Cell Biology, Radiation and Stress Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Katarzyna
K
Siudeja
Nicola A
NA
Grzeschik
Anil
A
Rana
Jannie
J
de Jong
Ody C M
OC
Sibon
D000199:Actins / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003065:Coenzyme A / Q000378:metabolism*; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008840:Microfilament Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency*; D034622:RNA Interference
D000199:Actins; D029721:Drosophila Proteins; D008840:Microfilament Proteins; C097180:tsr protein, Drosophila; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D003065:Coenzyme A