Non-canonical activation of the ER stress sensor ATF6 byLegionella pneumophilaeffectors

The intracellular bacterial pathogen Legionella pneumophila ( L.p. ) secretes ~330 effector proteins into the host cell to sculpt an Endoplasmic Reticulum (ER)-derived replicative niche. We previously reported five L.p. effectors that inhibit IRE1, a key sensor of the homeostatic unfolded protein response (UPR) pathway. In this study, we discovered a subset of L.p. toxins that selectively activate the UPR sensor ATF6, resulting in its cleavage, nuclear translocation and target gene transcription without affecting other UPR sensors such as PERK. In a deviation from the conventional model, this L.p . dependent activation of ATF6 does not require its transport to the Golgi or its cleavage by the S1P/S2P proteases. We believe that our findings highlight the unique regulatory control that L.p . exerts upon the three UPR sensors and expand the repertoire of bacterial proteins that selectively perturb host homeostatic pathways.