NOD1 and NOD2 signalling links ER stress with inflammation

A. Marijke Keestra-Gounder1*, Mariana X. Byndloss1*, Núbia Seyffert1, Briana M. Young1, Alfredo Chávez-Arroyo1, April Y. Tsai1, Stephanie A. Cevallos1, Maria G. Winter1, Oanh H. Pham2, Connor R. Tiffany1, Maarten F. de Jong1, Tobias Kerrinnes1, Resmi Ravindran2, Paul A. Luciw2, Stephen J. McSorley2, Andreas J. Bäumler1* & Renée M. Tsolis1*

Nature 532, 394–397 (21 April 2016) doi:10.1038/nature17631

Speaker: Chu-Yi Hsieh (謝筑伊)                                          Time: 15:00~16:00, Mar. 8, 2017

Commentator: Dr. Yau-Sheng Tsai (蔡曜聲老師)               Place: Room 601

Abstract:

Endoplasmic reticulum (ER) stress contributes to the etiology of many human diseases, such as Crohn’s disease, type 2 diabetes, Parkinson’s disease, and cancers. The ER is a specialized organelle that orchestrates the protein synthesis and homeostasis, folding and transport the proteins in eukaryotic cells. Altered ER homeostasis leads to the accumulation of unfolded or misfolded proteins in the ER lumen, known as ER stress, which activates the unfolded protein response (UPR)¹. UPR can activate three transmembrane receptors, ATF6, PERK and IRE1α. Activated IRE1α recruits TRAF2 to induce inflammatory responses via NF-κB pathway. Inflammation can also be triggered by pattern recognition receptors (PRRs), such as Toll-like receptors or nucleotide-binding oligomerization domain (NOD)-like receptors. But it is not clear whether PRRs have a key role in linking ER stress to inflammation. In this study, the author demonstrates that NOD1 and NOD2, two members of NOD-like receptors family, are important in ER stress-induced inflammation in mouse and human cells. The ER stress inducer thapsigargin can trigger pro-inflammatory cytokine IL-6 production in wild-type mice but decreased in NOD1 and NOD2 deficient mice. Inflammation and IL-6 production triggered by ER stress during Brucella abortus infection, which carries a virulence factor VceC that can inject into host cells, is dependent on TRAF2-NOD1/NOD2/RIP2, and can be reduced by ER stress inhibitor TUDCA or an IRE1α kinase inhibitor. The author also find that suppress ER stress response can increase the viability of pups in the pregnant mouse infected by B. abortus. These finding provides a new link between innate immunity, NOD1 and NOD2, and inflammatory diseases involving ER stress.

References:

1.     Miao Wang & Randal J. Kaufman. (2016) Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529,326–335.