title: PIP3-binding proteins promote age-dependent protein aggregation and limit survival in C. elegans.
abstract: Class-I phosphatidylinositol 3-kinase (PI3KI) converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 comprises two fatty-acid chains that embed in lipid-bilayer membranes, joined by glycerol to inositol triphosphate. Proteins with domains that specifically bind that head-group (e.g. pleckstrin-homology [PH] domains) are thus tethered to the inner plasma-membrane surface where they have an enhanced likelihood of interaction with other PIP3-bound proteins, in particular other components of their signaling pathways. Null alleles of the C. elegans age-1 gene, encoding the catalytic subunit of PI3KI, lack any detectable class-I PI3K activity and so cannot form PIP3. These mutant worms survive almost 10-fold longer than the longest-lived normal control, and are highly resistant to a variety of stresses including oxidative and electrophilic challenges. Traits associated with age-1 mutation are widely believed to be mediated through AKT-1, which requires PIP3 for both tethering and activation. Active AKT complex phosphorylates and thereby inactivates the DAF-16/FOXO transcription factor. However, extensive evidence indicates that pleiotropic effects of age-1-null mutations, including extreme longevity, cannot be explained by insulin like-receptor/AKT/FOXO signaling alone, suggesting involvement of other PIP3-binding proteins. We used ligand-affinity capture to identify membrane-bound proteins downstream of PI3KI that preferentially bind PIP3. Computer modeling supports a subset of candidate proteins predicted to directly bind PIP3 in preference to PIP2, and functional testing by RNAi knockdown confirmed candidates that partially mediate the stress-survival, aggregation-reducing and longevity benefits of PI3KI disruption. PIP3-specific candidate sets are highly enriched for proteins previously reported to affect translation, stress responses, lifespan, proteostasis, and lipid transport.
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare Service, Little Rock, AR, USA.|BioInformatics Program, University of Arkansas for Medical Sciences and University of Arkansas at Little Rock, Little Rock, AR, USA.|Reynolds Institute on Aging/Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ayyadevara
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare Service, Little Rock, AR, USA.|BioInformatics Program, University of Arkansas for Medical Sciences and University of Arkansas at Little Rock, Little Rock, AR, USA.
authors.forename: Meenakshisundaram
authors.initials: M
authors.lastname: Balasubramaniam
authors.affiliation: BioInformatics Program, University of Arkansas for Medical Sciences and University of Arkansas at Little Rock, Little Rock, AR, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Johnson
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare Service, Little Rock, AR, USA.|Reynolds Institute on Aging/Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Ramani
authors.initials: R
authors.lastname: Alla
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Mackintosh
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare Service, Little Rock, AR, USA.|BioInformatics Program, University of Arkansas for Medical Sciences and University of Arkansas at Little Rock, Little Rock, AR, USA.|Reynolds Institute on Aging/Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.|Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Shmookler Reis
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D020134:Catalytic Domain; D018389:Codon, Nonsense; D003198:Computer Simulation; D006861:Hydrogen Peroxide; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D013816:Thermodynamics
chemical_list: D018389:Codon, Nonsense; D008024:Ligands; D008055:Lipids; D008565:Membrane Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases
keywords: longevity; oxidative stress resistance; phosphatidylinositol 3,4,5-triphosphate (PIP3); phosphatidylinositol 3-kinase; protein aggregation