Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 8 (12)

Understanding the Role of the Unfolded Protein Response Sensor IRE1 in the Biology of Antigen Presenting Cells


Understanding the Role of the Unfolded Protein Response Sensor IRE1 in the Biology of Antigen Presenting Cells

Felipe Flores-Santibáñez et al. Cells.


The unfolded protein response (UPR) is an adaptive response that maintains the fidelity of the cellular proteome in conditions that subvert the folding capacity of the cell, such as those noticed in infection and inflammatory contexts. In immunity, the UPR sensor IRE1 (Inositol-requiring enzyme 1-alpha) has emerged as a critical regulator of the homeostasis of antigen presenting cells (APCs). In the past few years, it has become clear that IRE1 plays canonical and non-canonical roles in APCs, many of which intersect with key features of these cells, including the initiation of inflammation, antibody production, and antigen presentation. The aims of the present review are to provide recent insights on the mechanisms by which IRE1 regulates the diversity of APC functions and to highlight its relevance in the coordination of innate and adaptive immunity.

Keywords: antigen presenting cell; immunity; infection; inflammation; unfolded protein response.

Conflict of interest statement

The authors declare no conflicts of interest.


Figure 1
Figure 1
Activation of the three unfolded protein response (UPR) pathways is initiated by misfolded protein accumulation in the endoplasmic reticulum (ER). Phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) is dependent of the PKR-like kinase (PERK). This process inhibits ribosome assembly, which causes a translational block allowing the cell to cope with temporary ER-stress. However, ATF4 escapes this translation inhibition under conditions of stress and induces the transcription of genes related to cell survival including those involved in compensatory autophagy. Activation of the endoribonuclease domain of IRE1 is caused by the dissociation of the binding immunoglobulin protein (BiP) from the luminal domain of IRE1, causing the non-conventional splicing of the unspliced form of the X-box binding protein 1 (xbp1u) mRNA to produce xbp1s mRNA, which encodes the potent transcriptional activator, XBP1s. Among the various targets of XBP1s are genes encoding for chaperones, genes that assist in the degradation of misfolded proteins via ER-associated degradation (ERAD), lipid biogenesis, and cytokine production. Under conditions of chronical stress, IRE1 is hyper-activated, and it cleaves additional RNAs, such as mRNAs and miRNAs, through a process called Regulated IRE1 dependent decay (RIDD). After BiP dissociation from ATF6 during ER stress, ATF6 travels to the Golgi compartment, where it is processed by the S1P/S2P enzymes. The processed ATF6 fragment functions as a transcription factor that enhances protein folding at the ER level and also promote the expression of target genes that assist in degradation processes, including ERAD. Figure created with
Figure 2
Figure 2
The role of IRE1 in antigen presenting cells (APCs) in physiology and pathophysiology. IRE1 is activated by APCs in different contexts and the outputs of this response are both cell-type and context dependent. Dashed lines: Mechanism remains to be fully elucidated. Abbreviations: cDC1, conventional Dendritic Cells of type 1; cDC2, conventional Dendritic Cells type of 2; pDC, plasmocytoid Dendritic Cell; MoDC, Monocyte derived Dendritic Cell; IRE1, Inositol-requiring Enzyme 1 alpha; XBP1, X-box Binding Protein 1; RIDD, Regulated IRE1-dependent decay; SFAs, Saturated Fatty Acids; TLR, toll like receptor. All RIDD-related responses were studied in models where XBP1s was ablated. Figure created with

Similar articles

See all similar articles


    1. Bonnardel J., Guilliams M. Developmental control of macrophage function. Curr. Opin. Immunol. 2018;50:64–74. doi: 10.1016/j.coi.2017.12.001. - DOI - PubMed
    1. Davies L.C., Jenkins S.J., Allen J.E., Taylor P.R. Tissue-resident macrophages. Nat. Immunol. 2013;14:986–995. doi: 10.1038/ni.2705. - DOI - PMC - PubMed
    1. Merad M., Sathe P., Helft J., Miller J., Mortha A. The dendritic cell lineage: Ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 2013;31:563–604. doi: 10.1146/annurev-immunol-020711-074950. - DOI - PMC - PubMed
    1. Iwasaki A., Medzhitov R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 2015;16:343–353. doi: 10.1038/ni.3123. - DOI - PMC - PubMed
    1. Hiepe F., Dörner T., Hauser A.E., Hoyer B.F., Mei H., Radbruch A. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat. Rev. Rheumatol. 2011;7:170–178. doi: 10.1038/nrrheum.2011.1. - DOI - PubMed

Publication types