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.

Endoplasmic reticulum stress and NF‐kB activation in SARS‐CoV‐2 infected cells and their response to antiviral therapy

“…This type of interaction has already been described in cultured cells infected with other coronaviruses (reviewed in Reference 9 ) and pathogens. 22 As an original finding in this study, IRE‐1α activation in SARS‐CoV‐2 infected cells is associated with NF‐kB activation and pro‐inflammatory cytokine induction, which are key pathogenic events in COVID‐19, a viral disease that can evolve to severe inflammatory complications and oxidative stress especially in the elderly (recently reviewed in Reference 23 ). IRE‐1α induction and dimerization on the ER membrane stimulates NF‐kB activity by TRAF2 kinase activation and consequent IKK‐mediated phosphorylation and proteolytic removal of the NF‐kB inhibitor IkBα.…”

“… 21 IL‐10 induction involves MAPK‐ERK1/2 and p38, and NF‐κB signaling and transcriptional activation via promoter binding of the same NF‐κB and the AP‐1 transcriptional complex 21 ; the latter include c ‐Jun, a transcriptional protein downstream of stress‐activated MAPK‐JNK and IRE‐1α/TRAF2 pathway of UPR important for the pathogen‐induced stress response of the host cell. 22 Nelfinavir treatment was found to stimulate c ‐Jun protein expression (Figure 3b ), restoring at the same time all signal transduction and transcriptional elements of IL‐10 pathway of the infected cell, including NF‐kB (Figure 2a ), and the stress and survival MAPKs p38 and ERK1/2, respectively (Figure 3a,b ). These findings demonstrate that the Nelfinavir‐induced inhibition of IRE‐1α pathway of UPR in SARS‐CoV‐2 infected cells involves both the JNK/ c ‐Jun (AP‐1) and NF‐kB pathways (Figure 2b,c ) and their control function on cell death programs, including the caspase‐dependent apoptosis 6 (Figure 3b ).…”

“…IRE‐1α induction and dimerization on the ER membrane stimulates NF‐kB activity by TRAF2 kinase activation and consequent IKK‐mediated phosphorylation and proteolytic removal of the NF‐kB inhibitor IkBα. 22 , 24 Furthermore, IRE‐1α activation during pathogen‐induced ER stress may induce the expression of inflammatory cytokines, such as TNF‐α (Figure 3a ) and IL‐6 (Table 1 ), via XBP1 mRNA splicing modulation, 22 which may represent a mechanism alternative to NF‐kB activation to promote inflammation in the SARS‐CoV‐2 infected cell.…”

“…As an original finding in this study, IRE‐1α activation in SARS‐CoV‐2 infected cells is associated with NF‐kB activation and pro‐inflammatory cytokine induction, which are key pathogenic events in COVID‐19, a viral disease that can evolve to severe inflammatory complications and oxidative stress especially in the elderly (recently reviewed in Reference 23). IRE‐1α induction and dimerization on the ER membrane stimulates NF‐kB activity by TRAF2 kinase activation and consequent IKK‐mediated phosphorylation and proteolytic removal of the NF‐kB inhibitor IkBα 22,24 . Furthermore, IRE‐1α activation during pathogen‐induced ER stress may induce the expression of inflammatory cytokines, such as TNF‐α (Figure 3a) and IL‐6 (Table 1), via XBP1 mRNA splicing modulation, 22 which may represent a mechanism alternative to NF‐kB activation to promote inflammation in the SARS‐CoV‐2 infected cell.…”

The enteric pathogen Cryptosporidium parvum exports proteins into the cytosol of the infected host cell

“…ER stress is a common feature of intracellular infection that greatly modulates host cell survival and inflammatory response. Bacteria, viruses, and protozoa alike have evolved strategies to trigger or block the UPR during infection, suggesting the response not to be a by-product of infection, but rather an active participant ( Abhishek et al, 2018 ; Alshareef et al, 2021 ; Perera et al, 2017 ). This relationship is complex, and depending on cellular context, the UPR can aid pathogens or restrict them.…”