Poliovirus protein 3A binds and inactivates LIS1, causing block of membrane protein trafficking and deregulation of cell division.
Many viruses encode anti-apoptotic proteins that have been used as valuable tools for identification and analysis of key cellular regulators of programmed cell death. Here we demonstrate that the poliovirus protein 3A, previously shown to exhibit anti-apoptotic activity, binds and inactivates LIS1, a component of the dynein/dynactin motor complex, encoded by the gene mutated in patients with type I lissencephaly ("smooth brain"), thereby causing deregulation of endoplasmatic reticilum-to-Golgi vesicular transport, resulting in rapid disappearance of short-living receptors from the plasma membrane and loss of cell sensitivity to TNF and interferon. Truncated derivatives of LIS1, acting in a dominant negative manner, cause similar effects. However, 3A, being an endoplasmic reticulum-bound protein, locks Golgi-targeted YFP in the endoplasmatic reticilum, while expression of LIS1 mutants results in a dispersed cytoplasmic localization of the reporter protein. LIS1 dysfunction caused by ectopic expressing 3A or LIS1 mutants, as well as by overexpression of wild type LIS1, leads to cell blocking at the postmitotic stage associated with inability to undergo cytokinesis. Thus, the use of poliovirus protein as a research tool allowed us to reveal the role of cellular protein LIS1 in membrane protein trafficking, maintenance of Golgi integrity, surface presentation of unstable receptors, cell sensitivity to TNF-induced apoptosis and cell cycle progression.
Kondratova
Anna A
AA
Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Neznanov
Nickolay
N
Kondratov
Roman V
RV
Gudkov
Andrei V
AV
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D017955:Poliovirus; D011485:Protein Binding; D021381:Protein Transport; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism*
C109349:3A protein, Poliovirus; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D014758:Viral Core Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; C513190:Pafah1b1 protein, mouse