Inhibition of PP2A by LIS1 increases HIV-1 gene expression.
BACKGROUND
Lissencephaly is a severe brain malformation in part caused by mutations in the LIS1 gene. LIS1 interacts with microtubule-associated proteins, and enhances transport of microtubule fragments. Previously we showed that LIS1 interacts with HIV-1 Tat protein and that this interaction was mediated by WD40 domains of LIS1. In the present study, we analyze the effect of LIS1 on Tat-mediated transcription of HIV-1 LTR.


RESULTS
Tat-mediated HIV-1 transcription was upregulated in 293 cells transfected with LIS1 expression vector. The WD5 but not the N-terminal domain of LIS1 increases Tat-dependent HIV-1 transcription. The effect of LIS1 was similar to the effect of okadaic acid, an inhibitor of protein phosphatase 2A (PP2A). We then analyzed the effect of LIS1 on the activity of PP2A in vitro. We show that LIS1 and its isolated WD5 domain but not the N-terminal domain of LIS1 blocks PP2A activity.


CONCLUSIONS
Our results show that inhibition of PP2A by LIS1 induces HIV-1 transcription. Our results also point to a possibility that LIS1 might function in the cells as a yet unrecognized regulatory subunit of PP2A.
Epie
Nicolas
N
Center for Sickle Cell Disease, Howard University College of Medicine, 520 W Street N.W., Washington, DC 20059, USA. nepie@howard.edu
Ammosova
Tatyana
T
Turner
Willie
W
Nekhai
Sergei
S
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics; D054648:Protein Phosphatase 2; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D008869:Microtubule-Associated Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2