Effectors Targeting the Unfolded Protein Response during Intracellular Bacterial Infection

Abstract

The unfolded protein response (UPR) is a homeostatic response to endoplasmic reticulum (ER) stress within eukaryotic cells. The UPR initiates transcriptional and post-transcriptional programs to resolve ER stress; or, if ER stress is severe or prolonged, initiates apoptosis. ER stress is a common feature of bacterial infection although the role of the UPR in host defense is only beginning to be understood. While the UPR is important for host defense against pore-forming toxins produced by some bacteria, other bacterial effector proteins hijack the UPR through the activity of translocated effector proteins that facilitate intracellular survival and proliferation. UPR-mediated apoptosis can limit bacterial replication but also often contributes to tissue damage and disease. Here, we discuss the dual nature of the UPR during infection and the implications of UPR activation or inhibition for inflammation and immunity as illustrated by different bacterial pathogens.

Keywords: ER stress; UPR; bacteria; effector proteins; infection; secretion systems.

Figure 1

ER stress and the unfolded protein response (UPR). The UPR is an intracellular signaling cascade activated by misfolded proteins within the ER lumen. Misfolded proteins sequester BiP to release Perk, Ire1 and ATF6 to initiate downstream signaling. Perk is a kinase which phosphorylates the translation initiation factor eIF2α to repress protein synthesis, but selectively increases the translation of ATF4 mRNA via upstream open reading frames (uORFs) in its 5′ untranslated region (UTR). ATF4 is a transcription factor which increases the transcription of the pro-apoptotic factor CHOP. Ire1 is a bi-functional kinase/endoribonuclease (RNase) which splices XBP1 mRNA in the cytoplasm to generate the active transcription factor, XBP1s. Ire1 also cleaves other ER-targeted mRNAs which are then degraded, a process called regulated Ire1-dependent degradation (RIDD). ATF6 is cleaved by site-1 (S1P) and site-2 (S2P) proteases in the Golgi to release its N-terminal transcription factor domain (ATF6-N) that translocates into the nucleus. The single or combined action of XBP1s and ATF6-N up-regulates the transcription of many ER stress-responsive genes to increase ER protein-folding and secretory capacity and to remove misfolded proteins via ER-associated degradation (ERAD).

Figure 2

The UPR drives pro-inflammatory responses to ER stress. (a) TLR signaling activates Ire1 and XBP1 mRNA splicing via a MyD88-dependent pathway. Translocation of XBP1s into the nucleus enhances the transcription of pro-inflammatory cytokines including IL-6 and TNFα. TLR signaling via TRIF activates eIF2B GEF activity to counteract the activity of phosphorylated eIF2α. This allows protein synthesis, and therefore cytokine production, to proceed despite Perk activation and delays pro-apoptotic signaling via CHOP. (b) Ire1 interacts with TRAF2 to activate IKK and JNK signaling cascades. IKK and JNK activate the pro-inflammatory transcription factors NF-κB and AP-1, respectively, to drive the production of pro-inflammatory cytokines during ER stress. Perk signaling and eIF2α phosphorylation inhibits biosynthesis of inhibitor of κB (IκB) which increases NF-κB transcriptional activity and pro-inflammatory cytokine production.