The endoplasmic reticulum (ER) serves many general functions, including the facilitation of protein folding and the transport of synthesized proteins, but it also has an important role in sensing cellular stress. ER-stress identifies a group of signals that induce a transcriptional program enabling cells to survive protein overload and injury in the ER. This highly coordinated response involves three parallel signaling branches localized at the ER, namely IRE1, ATF6 and PERK.
New findings suggest that these signaling pathways can initiate inflammation and, in specialized cells and tissues, may be involved in the pathogenesis of inflammatory and infectious diseases. However, this is an emerging field of research and little is known on the specific nature of these signaling pathways and their function in regulating immunity. We recently found that TLR4 and TLR2 specifically activate the ER-stress sensor kinase IRE1 and its downstream target, the transcription factor XBP1. Previously described XBP1 ER stress target genes are not induced by TLR signaling. Instead, TLR-activated XBP1 is required for optimal and sustained production of proinflammatory cytokines in macrophages. Consistent with this finding, IRE1 activation by ER-stress synergizes with TLR activation for cytokine production. Moreover, XBP1 deficiency markedly increases bacterial burden in animals infected with the TLR2-activating human pathogen Francisella tularensis.
These findings uncovered an unsuspected critical new function for the XBP1 transcription factor in mammalian host defenses. The knowledge gained from these studies will provide a better understanding of regulatory pathways controlling immune responses and will aid in the development of therapies aimed at improving the outcome of diseases characterized by inflammation and ER-stress.
- Martinon, F., and der Goot, van, F.G. (2013). Did cholera toxin finally get caught? Cell Host Microbe 13, 501–503.
- Hu, Z., Yan, C., Liu, P., Huang, Z., Ma, R., Zhang, C., Wang, R., Zhang, Y., Martinon, F., Miao, D., et al. (2013). Crystal structure of NLRC4 reveals its autoinhibition mechanism. Science 341, 172–175.
- Martinon F. The endoplasmic reticulum: a sensor of cellular stress that modulates immune responses. Microbes Infect. 2012 Nov;14(14):1293-300. doi: 10.1016/j.micinf.2012.07.005. Epub 2012 Jul 16.
- Martinon F. Targeting endoplasmic reticulum signaling pathways in cancer. Acta Oncol. 2012 Sep;51(7):822-30. doi: 10.3109/0284186X.2012.689113. Epub 2012 Jun 11.
- Martinon F. Dangerous liaisons: mitochondrial DNA meets the NLRP3 inflammasome. Immunity. 2012 Mar 23;36(3):313-5. doi: 10.1016/j.immuni.2012.03.005.
- Hetz C, Martinon F, Rodriguez D, Glimcher LH. The Unfolded Protein Response: Integrating Stress Signals Through the Stress Sensor IRE1α. Physiol Rev. 2011 Oct;91(4):1219-43. doi: 10.1152/physrev.00001.2011.
- Martinon F, Glimcher LH. Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum. Curr Opin Immunol. 2011 Feb;23(1):35-40. doi: 10.1016/j.coi.2010.10.016. Epub 2010 Nov 18.
- Martinon F, Chen X, Lee AH, Glimcher LH. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010 May;11(5):411-8. doi: 10.1038/ni.1857. Epub 2010 Mar 28.
- Lisbona F, Rojas-Rivera D, Thielen P, Zamorano S, Todd D, Martinon F, Glavic A, Kress C, Lin JH, Walter P, Reed JC, Glimcher LH, Hetz C. BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha. Mol Cell. 2009 Mar 27;33(6):679-91. doi: 10.1016/j.molcel.2009.02.017.
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