Emerging functions of the unfolded protein response in immunity

Janssens, Sophie; Pulendran, Bali; Lambrecht, Bart N.

doi:10.1038/ni.2991

Cited by 209 publications

(208 citation statements)

References 140 publications

(215 reference statements)

Supporting

Mentioning

204

Contrasting

Order By: Relevance

“…Physiologically, XBP1 is necessary for differentiation of B cells, NK cells, and macrophages, although there is no detected basal IRE-1 activity for naive T cells and monocytes from spleen (17). There are only sporadic data on neutrophils (21), and in our study we found that .…”

Section: Discussionmentioning

confidence: 45%

“…The proximal "sensors" of ER stress are the chaperone grp78 (also known as BiP) along with protein kinase R-like ER kinase (PERK), activating transcription factor (ATF)6, and inositol-requiring kinase 1 (IRE1), as well as their downstream transcriptional effectors ATF4, ATF6, and X-boxbinding protein 1 (XBP1)s, respectively (17,18). As part of normal cellular housekeeping, a complex molecular network has evolved to promote the proper folding of proteins and to identify and degrade misfolded proteins.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Endoplasmic Reticulum Stress of Neutrophils Is Required for Ischemia/Reperfusion–Induced Acute Lung Injury

Chen

Jia

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Diverse clinical factors, including intestinal ischemia, contribute to acute lung injury (ALI), which has up to a 40% mortality rate. During the development of lung injury an immune response is elicited that exacerbates the lung insult. Neutrophils have been well studied in mediating the pulmonary insults through an assortment of mechanisms, such as release of granule contents and production of proinflammatory cytokines due to the overactivation of complement and cytokines. In this study, we found that enhanced endoplasmic reticulum (ER) stress was observed in infiltrated neutrophils in the early stage of an ALI mice model. In neutrophils, complement 5a (C5a) inspires strong ER stress through inositol-requiring kinase 1a and, to a less extent, the protein kinase R–like ER kinase signaling pathway. The granule release induced by C5a was ER stress mediated. Knowkdown of X-box–binding protein 1, a downstream signaling molecule of inositol-requiring kinase 1a, impaired granule release, based on myeloperoxidase production. Further analysis revealed that C5a induced ER stress by binding to C5a receptor in neutrophils. Using xbpf/f MRP8-cre mice in which X-box–binding protein 1 is deficient specifically in neutrophils and ER stress is deprived, we confirmed that ER stress in neutrophils was required for granule release in vivo and led to ALI, whereas dampening ER stress in neutrophils substantially alleviated ALI. Taken together, our results demonstrated that C5a receptor–mediated ER stress induced granule release in neutrophils, contributing to the development of ALI. This novel mechanism suggests a new potential therapeutic target in autophagy regulation for ALI.

show abstract

Section: Discussionmentioning

confidence: 45%

mentioning

confidence: 99%

Endoplasmic Reticulum Stress of Neutrophils Is Required for Ischemia/Reperfusion–Induced Acute Lung Injury

Chen

Jia

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…These include ER stress-induced transcription factor CHOP, crucial for BMDDC IL-23 expression (12), and XBP1, essential for survival of plasmacytoid and conventional DC (23). Activation of the UPR is not limited to an overload in protein folding capacity and, in fact, alternative ways to trigger ER stress sensors exist but are not well understood (24,62). In vivo studies show that constitutive activation of the IRE-1 pathways is present in CD8a+ DC as well as developing B and T cells (34).…”

Section: Discussionmentioning

confidence: 99%

GlutathioneS-Transferase P-Mediated Protein S-Glutathionylation of Resident Endoplasmic Reticulum Proteins Influences Sensitivity to Drug-Induced Unfolded Protein Response

Zhang

Ancrum

et al. 2017

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Aims: S-glutathionylation of cysteine residues, catalyzed by glutathione S-transferase Pi (GSTP), alters structure/function characteristics of certain targeted proteins. Our goal is to characterize how S-glutathionylation of proteins within the endoplasmic reticulum (ER) impact cell sensitivity to ER-stress inducing drugs. Results: We identify GSTP to be an ER-resident protein where it demonstrates both chaperone and catalytic functions. Redox based proteomic analyses identified a cluster of proteins cooperatively involved in the regulation of ER stress (immunoglobulin heavy chain-binding protein [BiP], protein disulfide isomerase [PDI], calnexin, calreticulin, endoplasmin, sarco/endoplasmic reticulum Ca 2+ -ATPase [SERCA]) that individually coimmunoprecipitated with GSTP (implying protein complex formation) and were subject to reactive oxygen species (ROS) induced S-glutathionylation. S-glutathionylation of each of these six proteins was attenuated in cells (liver, embryo fibroblasts or bone marrow dendritic) from mice lacking GSTP (Gstp1/p2 -/-) compared to wild type (Gstp1/p2 +/+ ). Moreover, Gstp1/p2 -/-cells were significantly more sensitive to the cytotoxic effects of the ER-stress inducing drugs, thapsigargin (7-fold) and tunicamycin (2-fold). Innovation: Within the family of GST isozymes, GSTP has been ascribed the broadest range of catalytic and chaperone functions. Now, for the first time, we identify it as an ER resident protein that catalyzes S-glutathionylation of critical ER proteins within this organelle. Of note, this can provide a nexus for linkage of redox based signaling and pathways that regulate the unfolded protein response (UPR). This has novel importance in determining how some drugs kill cancer cells. Conclusions: Contextually, these results provide mechanistic evidence that GSTP can exert redox regulation in the oxidative ER environment and indicate that, within the ER, GSTP influences the cellular consequences of the UPR through S-glutathionylation of a series of key interrelated proteins. Antioxid. Redox Signal. 26, 247-261.

show abstract

“…While Rab11a activity recruits and keeps MHC-I within endosomal recycling compartment (ERC) under steady condition, MyD88-dependent TLR signals drive IKK2-mediated phosphorylation of phagosome-associated SNAP23, orchestrating ERC-phagosome fusion, promoting enrichment of phagosomes with ERC-derived MHC-I, and finally allowing cross-presentation during infection. 139 Transcription factor TFEB, 140 cell stress sensor IRE-1α, [141][142][143] NF-κB-inducing kinase (NIK) 144 and the lectin Siglec-G 145 have been shown to regulate DC cross-presentation in initiating antigen-specific CTL responses via distinct molecular mechanisms. For example, Siglec-G inhibits cross-presentation by CD8α+ DC via impairing the formation of the MHC class I-exogenous antigen peptide complex, contributing to suppression of CTL responses to intracellular bacterial infection with Listeria monocytogenes or Mycobacterium bovis bacillus Calmette-Guérin and tumors.…”

Section: Dendritic Cellsmentioning

confidence: 99%