Priority Research Papers:
PIP3-binding proteins promote age-dependent protein aggregation and limit survival in C. elegans
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Srinivas Ayyadevara1,2,3, Meenakshisundaram Balasubramaniam1,2, Jay Johnson2, Ramani Alla1,3, Samuel G. Mackintosh4 and Robert J. Shmookler Reis1,2,3,4
1 McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare Service, Little Rock, AR, USA
2 BioInformatics Program, University of Arkansas for Medical Sciences and University of Arkansas at Little Rock, Little Rock, AR, USA
3 Reynolds Institute on Aging/Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
4 Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Robert J. Shmookler Reis, email:
Srinivas Ayyadevara, email:
Keywords: phosphatidylinositol 3-kinase; phosphatidylinositol 3,4,5-triphosphate (PIP3); longevity; oxidative stress resistance; protein aggregation
Received: March 28, 2016 Accepted: June 20, 2016 Published: July 12, 2016
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.
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