NOD1 and NOD2 signalling links ER stress with inflammation

Abstract

Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn’s disease and type 2 diabetes1,2. ER stress induces the unfolded protein response (UPR), which involves activation of three transmembrane receptors, ATF6 (activating transcription factor 6), PERK (protein kinase RNA-like endoplasmic reticulum kinase) and IRE1α (inositol-requiring enzyme 1α)3 (Extended Data figure 1a). Once activated, IRE1α recruits TRAF2 (TNF receptor-associated factor 2) to the ER membrane to initiate inflammatory responses via the nuclear factor kappa B (NF-κB) pathway4. Inflammation is commonly triggered when pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) or nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), detect tissue damage or microbial infection. However, it is not clear which PRRs play a major role in inducing inflammation during ER stress. Here we show that NOD1 and NOD2, two members of the NLR family of PRRs, are important mediators of ER stress-induced inflammation. The ER stress inducers thapsigargin and dithiothreitol (DTT) triggered production of the pro-inflammatory cytokine interleukin (IL)-6 in a NOD1/2-dependent fashion. Inflammation and IL-6 production triggered by infection with Brucella abortus, which induces ER stress by injecting the type IV secretion system (T4SS) effector protein VceC into host cells5, was TRAF2, NOD1/2 and RIP2-dependent and could be blunted by treatment with the ER-stress inhibitor tauroursodeoxycholate (TUDCA) or an IRE1α kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1α/TRAF2 signaling pathway provides a novel link between innate immunity and ER stress-induced inflammation.

ER-stress mobilization of death-associated protein kinase-1–dependent xenophagy counteracts mitochondria stress–induced epithelial barrier dysfunction

“…It will be important to address how the mitochondria-to-ATF6/DAPK1/autophagy interaction is impacted by other molecules that control epithelialmicrobe interaction (e.g. NOD proteins, NFkb and the inflammasome (38,46,47)). For instance, cells devoid of NOD2 are more sensitive to DNP-induced barrier defects (48) and reduced epithelia autophagy due to knockout of the amino-acid sensor GCN2 (a starvation model analogous to DNP exposure) was linked to ROS generation, inflammasome activation and intestinal inflammation (47).…”

The role of barrier function, autophagy, and cytokines in maintaining intestinal homeostasis

“…In addition to initiating anti-bacterial autophagy, NOD1 and NOD2 mediate ER-stressinduced inflammation in IECs [61]. In murine models ER stress triggers the production of pro-inflammatory cytokine IL-6, which is dependent on NOD1 and NOD2 [61].…”

“…Autophagy is also linked to ER stress through the NOD-like receptor family [61]. In addition to initiating anti-bacterial autophagy, NOD1 and NOD2 mediate ER-stressinduced inflammation in IECs [61].…”

“…This leads to an accumulation of misfolded proteins, a condition known as ER stress, which is associated with inflammatory diseases, such as IBD and type-2 diabetes. ER stress activates the unfolded protein response (UPR) [61], which plays a critical role in restoring ER homeostasis following accumulation of potentially toxic misfolded proteins [62].…”

Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer

“…Diet-induced induction of ER stress was associated with loss of guanylin in colorectum and uroguanylin in small intestine of obese mice . Furthermore, induction of ER stress pharmacologically by thapsigargan or tunicamycin (Keestra-Gounder et al, 2016), or genetically by eliminating XBP1 expression (van Galen et al, 2014;Keestra-Gounder et al, 2016), in lean mice recapitulated diet-induced obesity and produced hormone loss . ER stress induces a tripartite unfolded protein response directed at preserving ER homeostasis, mediated by inositol-requiring enzyme 1 and activating transcription factor 6, which both increase transcription of chaperones, and protein kinase R-like ER-localized eIF2a kinase, which inhibits protein translation (Wang and Kaufman, 2016).…”