Mapping the crossroads of immune activation and cellular stress response pathways

Abstract

The innate immune cell network detects specific microbes and damages to cell integrity in order to coordinate and polarize the immune response against invading pathogens. In recent years, a cross-talk between microbial-sensing pathways and endoplasmic reticulum (ER) homeostasis has been discovered and have attracted the attention of many researchers from the inflammation field. Abnormal accumulation of proteins in the ER can be seen as a sign of cellular malfunction and triggers a collection of conserved emergency rescue pathways. These signalling cascades, which increase ER homeostasis and favour cell survival, are collectively known as the unfolded protein response (UPR). The induction or activation by microbial stimuli of several molecules linked to the ER stress response pathway have led to the conclusion that microbe sensing by immunocytes is generally associated with an UPR, which serves as a signal amplification cascade favouring inflammatory cytokines production. Induction of the UPR alone was shown to promote inflammation in different cellular and pathological models. Here we discuss how the innate immune and ER-signalling pathways intersect. Moreover, we propose that the induction of UPR-related molecules by microbial products does not necessarily reflect ER stress, but instead is an integral part of a specific transcription programme controlled by innate immunity receptors.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1

Schematic description of the unfolded-protein response (UPR). Misfolded protein accumulation in the ER activates three distinct sensors: ATF6, inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). ER stress can be induced by stressors, such as ROS, leading to IRE1-dependent XBP1 mRNA splicing and translation. XBP1 nuclear translocation drives the transcriptional activation of multiple genes involved in ER and molecular chaperones homeostasy. Other UPR transcription factors, such as ATF4, and CHOP are induced upon eIF2α phosphorylation by PERK, which also inhibits translation initiation. The phosphatase 1 cofactor, GADD34, functions in a negative-feedback loop driven by ATF4, which dephosphorylates eIF2α and restores protein synthesis upon stress relief.

Figure 2

Schematic description of eIF2a phosphorylation pathway. Upon stress sensing, four known different eIF2α kinases, PKR, PERK, GCN2 and HRI, act via phosphorylation of serine 51 of eIF2α to limit global protein synthesis. GADD34 (PPP1R15a) and CReP (PPP1R15b) are regulatory subunits of PP1 that promote eIF2α dephosphorylation and counteract eIF2α kinases activity. Under normal conditions, ATF4, GADD34 and CHOP mRNA translation is repressed by competition for translation initiation of several short open reading frames (decoy ORFs) located upstream and frame shifted from the true translation initiation site. Upon phosphorylation of eIF2α, translation can now initiate at the AUG of the downstream coding regions allowing synthesis of these molecules during stress-induced protein synthesis inhibition.

Figure 3

Schematic description of dsRNA and viral sensing in the cytosol. During their replication, viruses generate RNA intermediates, which are sensed by several cytosolic DEAD-box RNA helicases, such as MDA5, which signal to promote type-I IFN production, through a cascade of adaptors leading to IRF3 phosphorylation and nuclear translocation. Concomitantly upon dsRNA sensing, PKR or GCN2 autophosphorylate and mediates phosphorylation of eIF2α, leading to inhibition of translation, while activating other signalling pathways promoting cytokines expression (e.g., p38 and JNK). The large production of inflammatory cytokines and antiviral factors, despite this rapid and efficient concomitant shut down of cellular protein synthesis, implies the existence of specific regulatory mechanisms allowing the translation of host antiviral mRNAs during eIF2α phosphorylation. ATF4 and GADD34 are necessary to allow cytokine translation.

Figure 4

Schematic description of the MSR. During the MSR, microbes- and virus-associated molecular patterns (e.g., LPS) are sensed directly or indirectly by different receptors, such as Toll-like-receptors (TLRs), Rig I-like receptors (RLRs) or the dsRNA-sensing kinase (PKR), which through complex signalling cascades, involving the TRIF adaptor and different TRAF ubiquitin ligase, leads to the nuclear translocation of NFkB or IRF-3, and subsequent IFN-I and inflammatory cytokines transcription. Microbial detection leads also to GADD34 expression, which, however, in this context has little effect on controlling global translation, while participates in the regulation of cytokine production both at the translational and transcriptional level. During the MSR, XBP1 splicing levels varies greatly according to cell models and microbe stimulus used; however, a striking distinctive feature of this pathway is the translational inhibition of CHOP synthesis, together with enhanced level of eIF2α de-phosphorylation, GADD34 and expression. GADD34, ATF4 and XBP1 are likely to favour the expression of cytokines through the targeting of yet undefined partners at the translational, signal transduction and transcriptional level. Cross-talks between the UPR and MSR clearly exist, and the direct activation of the TRAF2 or RIDD pathway by IRE1 and subsequent inflammatory cytokines transcription could be an example of those commonalities.