Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes?

Abstract

The unfolded protein response (UPR) is a cytoprotective response that is aimed at restoring cellular homeostasis following physiological stress exerted on the endoplasmic reticulum (ER), which also invokes innate immune signalling in response to invading microorganisms. Although it has been known for some time that the UPR is modulated by various viruses, recent evidence indicates that it also has multiple roles during bacterial infections. In this Review, we describe how bacteria interact with the ER, including how bacteria induce the UPR, how subversion of the UPR promotes bacterial proliferation and how the UPR contributes to innate immune responses against invading bacteria.

Figure 1. Cellular responses to endoplasmic reticulum stress

In response to increased in unfolded proteins in the ER lumen, three sensors located in the ER membrane, PERK, IRE1 and ATF6 activate the unfolded protein response. Under homeostatic conditions, PERK, IRE1 and ATF6 are bound by BiP, which suppresses their activity. In response to ER stress, BiP is recruited away from PERK, IRE1 and ATF6 to promote protein folding, which leads to activation of these ER stress sensors. PERK is a kinase, that auto-activates, dimerizes and phosphorylates its target eIF2, thereby preventing assembly of functional 80S ribosomes. Further, eIF2 directs selective translation of the transcription factor ATF4, which activates transcription of genes involved in the unfolded protein response. IRE1 is a bifunctional enzyme with kinase and endonuclease activity. In response to ER stress, IRE1 auto-phosphorylates via its kinase domain, which leads to dimerization and activation of its endonuclease activity. The endonuclease function of IRE1 degrades mRNA at the ER to decrease protein biosynthesis and also splices the transcript encoding XBP1, a second transcription factor directing expression of genes involved in restoring cellular homeostasis. ATF6 is a transcription factor that is anchored in the ER membrane, but in response to ER stress, it translocates to the Golgi, where the transcription factor domain is released from the membrane by sequential action of Site 1 (S1) and Site 2 (S2) proteases, allowing its translocation to the nuclease to activate transcription of UPR target genes. ATF4, XBP1 and ATF6 direct a transcriptional program that upregulates chaperones, components of the ERAD pathway, and factors involved in autophagy and apoptosis that act to restore cellular homeostasis or if the disruption to ER function cannot be resolved, initiate programmed cell death.

Figure 2. Trafficking and biogenesis of ER-associated replicative organelles by bacterial pathogens

Legionella pneumophila recruits early secretory vesicles to its plasma membrane-derived phagosome via delivery of the Dot/Icm Type IV secretion system effectors DrrA/SidM, LepB and RalF. These effectors modulate activities of the small GTPases Rab1 and ARF1 on the Legionella phagosome (see inset) to mediate bypass of the endocytic pathway and promote fusion of the Legionella phagosome with the ER and biogenesis of an ER-derived replicative vacuole. Brucella spp. reside within a vacuole (BCV) that traffics along the endocytic pathway, then is redirected to ER exit sites (ERES) and fuses with the ER via the action of VirB Type IV effector proteins and the small GTPases Sar1 and Rab2. The Brucella effector RicA binds GDP-bound Rab2 in an unknown manner and is required for accumulation of activated, GTP-bound Rab2 on BCVs (see inset). Chlamydia spp. and Simkania control the traffic and maturation of their original vacuole into a large inclusion that physically interacts with the ER at specific contact points (synapses).

Figure 3. Induction of the UPR and inflammation by bacterial virulence factors

Both AB-type toxins and T4SS effectors have been implicated in activation of the UPR and subsequent inflammation. The A subunit of CTX binds IRE1α and activates its endonuclease activity, leading to activation of Type I interferon and NF-κB, and Shiga toxin A subunit appears to elicit the same pathway. Subtilase cytotoxin also localizes to the ER and elicits the UPR by cleavage of the chaperone BiP, leading to activation of the UPR pathways and to NF-κB-dependent proinflammatory cytokine production. Two B. abortus T4SS effectors, VceC and BspK, target the ER, where VceC has been shown to bind to BiP. This binding may inhibit the interaction of BiP with PERK, IRE1α and ATF6, thereby promoting their activation. IRE1α interacts with TRAF2, leading to NF-κB activation.^,