NDLI: In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P

Content Provider	PubMed Central
Author	Zolov, Sergey N. Bridges, Dave Zhang, Yanling Lee, Wei-wei Riehle, Ellen Verma, Rakesh Lenk, Guy M. Kimber, Converso-baran Weide, Thomas Albin, Roger L. Saltiel, Alan R. Meisler, Miriam H. Russell, Mark W. Weisman, Lois S.
Abstract	Mutations that cause defects in levels of the signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] lead to profound neurodegeneration in mice. Moreover, mutations in human FIG4 predicted to lower PI(3,5)P2 levels underlie Charcot–Marie–Tooth type 4J neuropathy and are present in selected cases of amyotrophic lateral sclerosis. In yeast and mammals, PI(3,5)P2 is generated by a protein complex that includes the lipid kinase Fab1/Pikfyve, the scaffolding protein Vac14, and the lipid phosphatase Fig4. Fibroblasts cultured from Vac14 −/− and Fig4−/− mouse mutants have a 50% reduction in the levels of PI(3,5)P2, suggesting that there may be PIKfyve-independent pathways that generate this lipid. Here, we characterize a Pikfyve gene-trap mouse (Pikfyve β-geo/β-geo), a hypomorph with ∼10% of the normal level of Pikfyve protein. shRNA silencing of the residual Pikfyve transcript in fibroblasts demonstrated that Pikfyve is required to generate all of the PI(3,5)P2 pool. Surprisingly, Pikfyve also is responsible for nearly all of the phosphatidylinositol-5-phosphate (PI5P) pool. We show that PI5P is generated directly from PI(3,5)P2, likely via 3′-phosphatase activity. Analysis of tissues from the Pikfyve β-geo/β-geo mouse mutants reveals that Pikfyve is critical in neural tissues, heart, lung, kidney, thymus, and spleen. Thus, PI(3,5)P2 and PI5P have major roles in multiple organs. Understanding the regulation of these lipids may provide insights into therapies for multiple diseases.
Related Links	http://dx.doi.org/10.1073/pnas.1203106109
Ending Page	17477
Page Count	6
Starting Page	17472
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	43
Volume Number	109
Language	English
Publisher	National Academy of Sciences
Publisher Date	2012-10-23
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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