A positive role of mammalian Tip41-like protein, TIPRL, in the amino-acid dependent mTORC1-signaling pathway through interaction with PP2A

•TIPRL enhances amino-acid dependent mTORC1 signaling.•TIPRL associates with PP2Ac, preferentially its methylated form.•The PP2Ac binding-deficient TIPRL mutant loses the TIPRL action on mTORC1 signaling. Target of rapamycin complex 1 (TORC1) has a key role in cellular regulations in response to environmental conditions. In yeast, Tip41 downregulates TORC1 signaling via activation of PP2A phosphatase. We show here that overexpression of TIPRL, a mammalian Tip41, suppressed dephosphorylation of mechanistic TORC1 (mTORC1) substrates under amino acid withdrawal, and knockdown of TIPRL conversely attenuated phosphorylation of those substrates after amino acid refeeding. TIPRL associated with the catalytic subunit of PP2A (PP2Ac), which was required for the TIPRL action on mTORC1 signaling. Collectively, unlike yeast TIP41, TIPRL has a positive effect on mTORC1 signaling through the association with PP2Ac. PP2Acphysically interacts with TIPRL by anti bait coimmunoprecipitation (View Interaction: 1, 2) PR65physically interacts with PP2Ac by anti tag coimmunoprecipitation (View interaction) TIPRLphysically interacts with PP2Ac by anti tag coimmunoprecipitation (View Interaction: 1, 2) alpha 4physically interacts with PP2Ac by anti bait coimmunoprecipitation (View interaction) PP2Acphysically interacts with PR65 and TIPRL by anti tag coimmunoprecipitation (View interaction) PP2Acphysically interacts with TIPRL by anti tag coimmunoprecipitation (View interaction) alpha 4physically interacts with TIPRL by anti bait coimmunoprecipitation (View Interaction: 1, 2)