The B55α Subunit of PP2A Drives a p53-Dependent Metabolic Adaptation to Glutamine Deprivation

SummaryGlutamine is an essential nutrient for cancer cell survival and proliferation, yet the signaling pathways that sense glutamine levels remain uncharacterized. Here, we report that the protein phosphatase 2A (PP2A)-associated protein, α4, plays a conserved role in glutamine sensing. α4 promotes assembly of an adaptive PP2A complex containing the B55α regulatory subunit via providing the catalytic subunit upon glutamine deprivation. Moreover, B55α is specifically induced upon glutamine deprivation in a ROS-dependent manner to activate p53 and promote cell survival. B55α activates p53 through direct interaction and dephosphorylation of EDD, a negative regulator of p53. Importantly, the B55α-EDD-p53 pathway is essential for cancer cell survival and tumor growth under low glutamine conditions in vitro and in vivo. This study delineates a previously unidentified signaling pathway that senses glutamine levels as well as provides important evidence that protein phosphatase complexes are actively involved in signal transduction.

Graphical AbstractFigure optionsDownload high-quality image (155 K)Download as PowerPoint slideHighlights
► B55α is induced upon glutamine depletion and is required for tumor growth
► Glutamine deprivation-induced B55α is ROS dependent
► p53 is activated in response to low glutamine to promote cell survival
► B55α induces p53 activation through modification of a p53 regulator, EDD