Non-canonical activation of the ER stress sensor ATF6 by <i>Legionella pneumophila</i> effectors

Abstract

The intracellular bacterial pathogen <i>Legionella pneumophila</i> (<i>L.p.</i>) secretes ∼330 effector proteins into the host cell to sculpt an ER-derived replicative niche. We previously reported five <i>L.p.</i> effectors that inhibit IRE1, a key sensor of the homeostatic unfolded protein response (UPR) pathway. In this study, we discovered a subset of <i>L.p.</i> toxins that selectively activate the UPR sensor ATF6, resulting in its cleavage, nuclear translocation, and target gene transcription. In a deviation from the conventional model, this <i>L.p</i>-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 <i>L.p</i> exerts upon the three UPR sensors and expand the repertoire of bacterial proteins that selectively perturb host homeostatic pathways.