10.3389/fcimb.2018.00103.s001 Aseem Pandey Aseem Pandey Furong Lin Furong Lin Ana L. Cabello Ana L. Cabello Luciana F. da Costa Luciana F. da Costa Xuehuan Feng Xuehuan Feng Hui-Qiang Feng Hui-Qiang Feng Ming-Zhe Zhang Ming-Zhe Zhang Takao Iwawaki Takao Iwawaki Allison Rice-Ficht Allison Rice-Ficht Thomas A. Ficht Thomas A. Ficht Paul de Figueiredo Paul de Figueiredo Qing-Ming Qin Qing-Ming Qin Image1_Activation of Host IRE1α-Dependent Signaling Axis Contributes the Intracellular Parasitism of Brucella melitensis.TIF Frontiers 2018 Brucella melitensis unfolded protein response (UPR) inositol-requiring enzyme 1 (IRE1) ULK1 autophagy intracellular trafficking and replication 2018-04-20 04:03:32 Figure https://frontiersin.figshare.com/articles/figure/Image1_Activation_of_Host_IRE1_-Dependent_Signaling_Axis_Contributes_the_Intracellular_Parasitism_of_Brucella_melitensis_TIF/6164249 <p>Brucella spp. are intracellular vacuolar pathogens that causes brucellosis, a worldwide zoonosis of profound importance. We previously demonstrated that the activity of host unfolded protein response (UPR) sensor IRE1α (inositol-requiring enzyme 1) and ER-associated autophagy confer susceptibility to Brucella melitensis and Brucella abortus intracellular replication. However, the mechanism by which host IRE1α regulates the pathogen intracellular lifestyle remains elusive. In this study, by employing a diverse array of molecular approaches, including biochemical analyses, fluorescence microscopy imaging, and infection assays using primary cells derived from Ern1 (encoding IRE1) conditional knockout mice, we address this gap in our understanding by demonstrating that a novel IRE1α to ULK1, an important component for autophagy initiation, signaling axis confers susceptibility to Brucella intracellular parasitism. Importantly, deletion or inactivation of key signaling components along this axis, including IRE1α, BAK/BAX, ASK1, and JNK as well as components of the host autophagy system ULK1, Atg9a, and Beclin 1, resulted in striking disruption of Brucella intracellular trafficking and replication. Host kinases in the IRE1α-ULK1 axis, including IRE1α, ASK1, JNK1, and/or AMPKα as well as ULK1, were also coordinately phosphorylated in an IRE1α-dependent fashion upon the pathogen infection. Taken together, our findings demonstrate that the IRE1α-ULK1 signaling axis is subverted by the bacterium to promote intracellular parasitism, and provide new insight into our understanding of the molecular mechanisms of intracellular lifestyle of Brucella.</p>