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Readers, writers and erasers of nuclear PIP3.
Author(s) -
Blind Raymond D
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.946.11
Subject(s) - transcription factor , nuclear receptor , nuclear pore , transcriptional regulation , chemistry , gene knockdown , nuclear transport , microbiology and biotechnology , biology , gene , computational biology , biochemistry , cell nucleus , cytoplasm
Structural analyses of the NR5A nuclear receptors (NR5A1 and NR5A2) show that PIP2 and PIP3 bind these transcription factors in a format where the acyl chains are buried deep in the core of the NR5A protein, while the phospholipid headgroups are solvent exposed. We previously demonstrated that the phosphoinositide headgroups of these complexes are accessible to nuclear lipid signaling enzymes, which directly modify these transcription factor‐bound PIPs, altering the transcriptional output from NR5As. Here, we took a proteomics approach to ask if the solvent exposed PIP3 headgroup is available to interact with nuclear proteins. We identified two PH‐domain containing proteins that interact with NR5A1/PIP3, but not other phospholipid bound forms of NR5A1, and siRNA knockdown of these two genes decreases NR5A1 transcriptional activity. PH‐domains are one of the most well represented domain classes in the human genome, and are widely thought to mediate membrane binding, however only 10% of the PH‐domain proteins in yeast bind membranes. Our data suggest a fraction of PH‐domain containing proteins act as readers of nuclear PIP3, while nuclear lipid signaling enzymes acts as writers and erasers of nuclear PIP3. These data provide a direct mechanism that explains how nuclear PIP3 mediates transcriptional activation in mammalian cells. Support or Funding Information Jimmy V Foundation V‐Scholar Young Investigator Award, Vanderbilt Diabetes Research and Training Center Pilot & Feasibility Award on NIDDK P30 DK020593, Vanderbilt Diabetes Center Discovery Award, American Cancer Society/Vanderbilt‐Ingram Cancer Center Institutional Research Grant IRG‐58‐009‐56.