The unfolded protein response in immunity and inflammation

Grootjans, Joep; Kaser, Arthur; Kaufman, Randal J.; Blumberg, Richard S.

doi:10.1038/nri.2016.62

Cited by 639 publications

(628 citation statements)

References 188 publications

(203 reference statements)

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“…O. tsutsugamushi elicits but is not cleared by autophagy (56,57), autophagy is induced by and decreases ER stress (58), and amino acids resulting from autophagy benefit the intracellular growth of Anaplasma phagocytophilum and Ehrlichia chaffeensis (59,60), which are obligate intracellular bacteria that are in the order Rickettsiales with O. tsutsugamushi. Amino acids resulting from the autophagy response to O. tsutsugamushi-induced ER stress might a The predicted biological score (PBS) was calculated for each candidate protein to assess the reliability of each interaction, ranging from the highest probability of specificity (score of A) to the lowest probability of specificity (score of E) between two proteins.…”

Section: Discussionmentioning

confidence: 99%

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

et al. 2018

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Orientia tsutsugamushi, an obligate intracellular bacterium that is auxotrophic for the aromatic amino acids and histidine, causes scrub typhus, a potentially deadly infection that threatens 1 billion people. O. tsutsugamushi growth is minimal during the first 24 to 48 h of infection but its growth becomes logarithmic thereafter. How the pathogen modulates cellular functions to support its growth is poorly understood. The unfolded protein response (UPR) is a cytoprotective pathway that relieves endoplasmic reticulum (ER) stress by promoting ER-associated degradation (ERAD) of misfolded proteins. Here, we show that O. tsutsugamushi invokes the UPR in the first 48 h and benefits from ER stress in an amino acid-dependent manner. O. tsutsugamushi also impedes ERAD during this time period. By 72 h, ER stress is alleviated and ERAD proceeds unhindered. Sustained inhibition of ERAD using RNA interference results in an O. tsutsugamushi growth defect at 72 h that can be rescued by amino acid supplementation. Thus, O. tsutsugamushi temporally stalls ERAD until ERAD-derived amino acids are needed to support its growth. The O. tsutsugamushi effector Ank4 is linked to this phenomenon. Ank4 interacts with Bat3, a eukaryotic chaperone that is essential for ERAD, and is transiently expressed by O. tsutsugamushi during the infection period when it inhibits ERAD. Ectopically expressed Ank4 blocks ERAD to phenocopy O. tsutsugamushi infection. Our data reveal a novel mechanism by which an obligate intracellular bacterial pathogen modulates ERAD to satisfy its nutritional virulence requirements.

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Section: Discussionmentioning

confidence: 99%

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

et al. 2018

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“…ATF-6 mediates inhibition of the DNPeffect -ER stress triggers three major pathways: IRE1 that activates the MAP kinase, JNK, and splicing of XBP1 transcription factor; PERK, that leads to eIF2a phosphorylation which acts as a transcription factor and ATF4 mobilization, another transcription factor; and, ATF6, that when truncated serves as a transcription factor (25).…”

Section: T316amentioning

confidence: 99%

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

Lopes

Keita

Saxena

et al. 2018

Journal of Biological Chemistry

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The gut microbiome contributes to inflammatory bowel disease (IBD), in which bacteria can be present within the epithelium. Epithelial barrier function is decreased in IBD, and dysfunctional epithelial mitochondria and endoplasmic reticulum (ER) stress have been individually associated with IBD. We therefore hypothesized that the combination of ER and mitochondrial stresses significantly disrupt epithelial barrier function. Here, we treated human colonic biopsies, epithelial colonoids, and epithelial cells with an uncoupler of oxidative phosphorylation, dinitrophenol (DNP), with or without the ER stressor tunicamycin, and assessed epithelial barrier function by monitoring internalization and translocation of commensal bacteria. We also examined barrier function and colitis in mice exposed to dextran sodium sulphate (DSS) or DNP and co-treated with DAPK6, an inhibitor of death-associated protein kinase 1 (DAPK1). Contrary to our hypothesis, induction of ER stress (i.e. the unfolded protein response) protected against decreased barrier function caused by the disruption of mitochondrial function. ER stress did not prevent DNP-driven uptake of bacteria; rather, specific mobilization of the ATF6 arm of ER stress and recruitment of DAPK-1 resulted in enhanced autophagic killing (xenophagy) of bacteria. Of note, epithelia with a Crohn's disease-susceptibility mutation in the autophagy http://www.jbc.org/cgi

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“…[5][6][7][8][9][10][11] The 3 primary regulators of the ER stress response are IRE-1a, PERK, and ATF6. 12 IRE-1a is particularly critical for the function of plasma cells. [13][14][15] When activated, IRE-1a converts unspliced XBP-1 (XBP-1u) messenger RNA (mRNA) into spliced XBP-1 (XBP1s) mRNA via its ribonuclease activity.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

Schutt

Tang

et al. 2018

Blood Advances

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Key Points• Targeting XBP-1 on B cells is sufficient to prevent cGVHD.• Pharmacologic inhibition of IRE-1a/ XBP-1 prevents cGVHD while preserving GVL activity. which correlated with reductions in donor T-cell and dendritic cell skin infiltrates. Inhibition of the IRE-1a/XBP-1 pathway also preserved the GVL effect against chronic myelogenous leukemia mediated by allogeneic splenocytes. Collectively, the ER stress response mediated by the IRE-1a/XBP-1 axis is required for cGVHD development but dispensable for GVL activity.

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The unfolded protein response in immunity and inflammation

Cited by 639 publications

References 188 publications

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

Orientia tsutsugamushi Modulates Endoplasmic Reticulum-Associated Degradation To Benefit Its Growth

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

Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

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