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Coordination of stress, Ca2+, and immunogenic signaling pathways by PERK at the endoplasmic reticulum

  • Alexander R. van Vliet , Abhishek D. Garg and Patrizia Agostinis EMAIL logo
Published/Copyright: February 12, 2016
Biological Chemistry
From the journal Biological Chemistry Volume 397 Issue 7

Abstract

The endoplasmic reticulum (ER) is the main coordinator of intracellular Ca2+ signaling, protein synthesis, and folding. The ER is also implicated in the formation of contact sites with other organelles and structures, including mitochondria, plasma membrane (PM), and endosomes, thereby orchestrating through interorganelle signaling pathways, a variety of cellular responses including Ca2+ homeostasis, metabolism, and cell death signaling. Upon loss of its folding capacity, incited by a number of stress signals including those elicited by various anticancer therapies, the unfolded protein response (UPR) is launched to restore ER homeostasis. The ER stress sensor protein kinase RNA-like ER kinase (PERK) is a key mediator of the UPR and its role during ER stress has been largely recognized. However, growing evidence suggests that PERK may govern signaling pathways through UPR-independent functions. Here, we discuss emerging noncanonical roles of PERK with particular relevance for the induction of danger or immunogenic signaling and interorganelle communication.

Keywords: calcium signaling; endoplasmic reticulum; immunogenic cell death; MAMs; mitochondria; PERK; plasma membrane; SOCE

Acknowledgments

This work was supported by C16/15/073 grant of the KU Leuven, Federal Grant under the IAP7/32 of the Belgian Science Policy Office and FWO grant G0584.12 to Patrizia Agostinis. A.D.G. is a post-doctoral fellow of the FWO-Flanders.

References

Ammar, M.R., Kassas, N., Chasserot-Golaz, S., Bader, M.F., and Vitale, N. (2013). Lipids in regulated exocytosis: what are they doing? Front Endocrinol. (Lausanne) 4, 125.10.3389/fendo.2013.00125Search in Google Scholar PubMed PubMed Central

Anelli, T., Bergamelli, L., Margittai, E., Rimessi, A., Fagioli, C., Malgaroli, A., Pinton, P., Ripamonti, M., Rizzuto, R., and Sitia, R. (2012). Ero1α regulates Ca2+ fluxes at the endoplasmic reticulum-mitochondria interface (MAM). Antioxid. Redox Signal. 16, 1077–1087.10.1089/ars.2011.4004Search in Google Scholar PubMed

Bettigole, S.E., and Glimcher, L.H. (2015). Endoplasmic reticulum stress in immunity. Annu. Rev. Immunol. 33, 107–138.10.1146/annurev-immunol-032414-112116Search in Google Scholar PubMed

Bollo, M., Paredes, R.M., Holstein, D., Zheleznova, N., Camacho, P., and Lechleiter, J.D. (2010). Calcineurin interacts with PERK and dephosphorylates calnexin to relieve ER stress in mammals and frogs. PLoS One 5, e11925.10.1371/journal.pone.0011925Search in Google Scholar PubMed PubMed Central

Bravo, R., Vicencio, J.M., Parra, V., Troncoso, R., Munoz, J.P., Bui, M., Quiroga, C., Rodriguez, A.E., Verdejo, H.E., Ferreira, J., et al. (2011). Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress. J. Cell. Sci. 124, 2143–2152.10.1242/jcs.080762Search in Google Scholar PubMed PubMed Central

Cullinan, S.B., Zhang, D., Hannink, M., Arvisais, E., Kaufman, R.J., and Diehl, J.A. (2003). Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol. Cell. Biol. 23, 7198–7209.10.1128/MCB.23.20.7198-7209.2003Search in Google Scholar PubMed PubMed Central

de Brito, O.M. and Scorrano, L. (2008). Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605–610.10.1038/nature07534Search in Google Scholar PubMed

Dudek-Peric, A.M., Ferreira, G.B., Muchowicz, A., Wouters, J., Prada, N., Martin, S., Kiviluoto, S., Winiarska, M., Boon, L., Mathieu, C., et al. (2015). Antitumor immunity triggered by melphalan is potentiated by melanoma cell surface-associated calreticulin. Cancer Res. 75, 1603–1614.10.1158/0008-5472.CAN-14-2089Search in Google Scholar PubMed

Filadi, R., Greotti, E., Turacchio, G., Luini, A., Pozzan, T., and Pizzo, P. (2015). Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling. Proc. Natl. Acad. Sci. USA 112, E2174–2181.10.1073/pnas.1504880112Search in Google Scholar PubMed PubMed Central

Friedman, J.R., Lackner, L.L., West, M., DiBenedetto, J.R., Nunnari, J., and Voeltz, G.K. (2011). ER tubules mark sites of mitochondrial division. Science 334, 358–362.10.1126/science.1207385Search in Google Scholar PubMed PubMed Central

Fucikova, J., Moserova, I., Urbanova, L., Bezu, L., Kepp, O., Cremer, I., Salek, C., Strnad, P., Kroemer, G., Galluzzi, L., et al. (2015). Prognostic and predictive value of DAMPs and DAMP-Associated processes in cancer. Front Immunol. 6, 402.10.3389/fimmu.2015.00402Search in Google Scholar PubMed PubMed Central

Galluzzi, L., Vacchelli, E., Bravo-San Pedro, J.M., Buque, A., Senovilla, L., Baracco, E.E., Bloy, N., Castoldi, F., Abastado, J.P., Agostinis, P., et al. (2014). Classification of current anticancer immunotherapies. Oncotarget 5, 12472–12508.10.18632/oncotarget.2998Search in Google Scholar PubMed PubMed Central

Garg, A.D., Krysko, D.V., Vandenabeele, P., and Agostinis, P. (2012a). Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol. Immunother. 61, 215–221.10.1007/s00262-011-1184-2Search in Google Scholar PubMed

Garg, A.D., Krysko, D.V., Verfaillie, T., Kaczmarek, A., Ferreira, G.B., Marysael, T., Rubio, N., Firczuk, M., Mathieu, C., Roebroek, A.J., et al. (2012b). A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 31, 1062–1079.10.1038/emboj.2011.497Search in Google Scholar PubMed PubMed Central

Garg, A.D., Dudek, A.M., Ferreira, G.B., Verfaillie, T., Vandenabeele, P., Krysko, D.V., Mathieu, C., and Agostinis, P. (2013). ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death. Autophagy 9, 1292–1307.10.4161/auto.25399Search in Google Scholar PubMed

Garg, A.D., De Ruysscher, D., and Agostinis, P. (2015a). Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: a large-scale meta-analysis. Oncoimmunology, DOI: 10.1080/2162402X.2015.1069938.Search in Google Scholar PubMed PubMed Central

Garg, A.D., Elsen, S., Krysko, D.V., Vandenabeele, P., de Witte, P., and Agostinis, P. (2015b). Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal. Oncotarget 6, 26841–26860.10.18632/oncotarget.4754Search in Google Scholar PubMed PubMed Central

Garg, A.D., Galluzzi, L., Apetoh, L., Baert, T., Birge, R.B., Bravo-San Pedro, J.M., Breckpot, K., Brough, D., Chaurio, R., Cirone, M., et al. (2015c). Molecular and translational classifications of DAMPs in immunogenic cell death. Front Immunol. 6, 588.10.3389/fimmu.2015.00588Search in Google Scholar PubMed PubMed Central

Garg, A.D., Maes, H., van Vliet, A.R., and Agostinis, P. (2015d). Targeting the hallmarks of cancer with therapy-induced endoplasmic reticulum (ER) stress. Mol. Cell Oncol. 2, e975089.10.4161/23723556.2014.975089Search in Google Scholar PubMed PubMed Central

Garg, A.D., Krysko, D.V., Vandenabeele, P., and Agostinis, P. (2016a). Extracellular ATP and P2X7 receptor exert context-specific immunogenic effects after immunogenic cancer cell death. Cell Death Dis. 7, e2097.10.1038/cddis.2015.411Search in Google Scholar PubMed PubMed Central

Garg, A.D., Vandenberk, L., Koks, C., Verschuere, T., Boon, L., Van Gool, S.W., and Agostinis, P. (2016b). Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma. Sci. Transl Med. 8, 328ra327.10.1126/scitranslmed.aae0105Search in Google Scholar PubMed

Gilady, S.Y., Bui, M., Lynes, E.M., Benson, M.D., Watts, R., Vance, J.E., and Simmen, T. (2010). Ero1α requires oxidizing and normoxic conditions to localize to the mitochondria-associated membrane (MAM). Cell Stress Chaperones 15, 619–629.10.1007/s12192-010-0174-1Search in Google Scholar PubMed PubMed Central

Gorlach, A., Klappa, P., and Kietzmann, T. (2006). The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid. Redox Signal. 8, 1391–1418.10.1089/ars.2006.8.1391Search in Google Scholar PubMed

Hamasaki, M., Furuta, N., Matsuda, A., Nezu, A., Yamamoto, A., Fujita, N., Oomori, H., Noda, T., Haraguchi, T., Hiraoka, Y., et al. (2013). Autophagosomes form at ER-mitochondria contact sites. Nature 495, 389–393.10.1038/nature11910Search in Google Scholar PubMed

Harding, H.P., Zhang, Y., and Ron, D. (1999). Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271–274.10.1038/16729Search in Google Scholar PubMed

Hetz, C., Chevet, E., and Oakes, S.A. (2015). Proteostasis control by the unfolded protein response. Nat. Cell Biol. 17, 829–838.10.1038/ncb3184Search in Google Scholar PubMed PubMed Central

Kepp, O., Senovilla, L., Vitale, I., Vacchelli, E., Adjemian, S., Agostinis, P., Apetoh, L., Aranda, F., Barnaba, V., Bloy, N., et al. (2014). Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 3, e955691.10.4161/21624011.2014.955691Search in Google Scholar PubMed PubMed Central

Kroemer, G., Galluzzi, L., Kepp, O., and Zitvogel, L. (2013). Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72.10.1146/annurev-immunol-032712-100008Search in Google Scholar PubMed

Liu, Y., Su, Y., and Wang, X. (2013). Phosphatidic acid-mediated signaling. Adv. Exp. Med. Biol. 991, 159–176.10.1007/978-94-007-6331-9_9Search in Google Scholar PubMed

Liu, Z., Cai, H., Zhu, H., Toque, H., Zhao, N., Qiu, C., Guan, G., Dang, Y., and Wang, J. (2014). Protein kinase RNA-like endoplasmic reticulum kinase (PERK)/calcineurin signaling is a novel pathway regulating intracellular calcium accumulation which might be involved in ventricular arrhythmias in diabetic cardiomyopathy. Cell Signal. 26, 2591–2600.10.1016/j.cellsig.2014.08.015Search in Google Scholar PubMed

Luik, R.M., Wu, M.M., Buchanan, J., and Lewis, R. S. (2006). The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J. Cell Biol. 174, 815–825.10.1083/jcb.200604015Search in Google Scholar PubMed PubMed Central

Malhi, H., Kropp, E.M., Clavo, V.F., Kobrossi, C.R., Han, J., Mauer, A.S., Yong, J., and Kaufman, R.J. (2013). C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis. J. Biol. Chem. 288, 18624–18642.10.1074/jbc.M112.442954Search in Google Scholar PubMed PubMed Central

Malhotra, J.D. and Kaufman, R.J. (2007). The endoplasmic reticulum and the unfolded protein response. Semin. Cell Dev. Biol. 18, 716–731.10.1016/j.semcdb.2007.09.003Search in Google Scholar PubMed PubMed Central

Munoz, J.P., Ivanova, S., Sanchez-Wandelmer, J., Martinez-Cristobal, P., Noguera, E., Sancho, A., Diaz-Ramos, A., Hernandez-Alvarez, M.I., Sebastian, D., Mauvezin, C., et al. (2013). Mfn2 modulates the UPR and mitochondrial function via repression of PERK. EMBO J. 32, 2348–2361.10.1038/emboj.2013.168Search in Google Scholar PubMed PubMed Central

Orci, L., Ravazzola, M., Le Coadic, M., Shen, W. W., Demaurex, N., and Cosson, P. (2009). From the Cover: STIM1-induced precortical and cortical subdomains of the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA 106, 19358–19362.10.1073/pnas.0911280106Search in Google Scholar PubMed PubMed Central

Oyadomari, S. and Mori, M. (2004). Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 11, 381–389.10.1038/sj.cdd.4401373Search in Google Scholar PubMed

Panaretakis, T., Kepp, O., Brockmeier, U., Tesniere, A., Bjorklund, A.C., Chapman, D.C., Durchschlag, M., Joza, N., Pierron, G., van Endert, P., et al. (2009). Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J. 28, 578–590.10.1038/emboj.2009.1Search in Google Scholar PubMed PubMed Central

Pollard, M.G., Travers, K.J. and Weissman, J.S. (1998). Ero1p: a novel and ubiquitous protein with an essential role in oxidative protein folding in the endoplasmic reticulum. Mol. Cell 1, 171–182.10.1016/S1097-2765(00)80018-0Search in Google Scholar

Raturi, A. and Simmen, T. (2013). Where the endoplasmic reticulum and the mitochondrion tie the knot: the mitochondria-associated membrane (MAM). Biochim Biophys Acta 1833, 213–224.10.1016/j.bbamcr.2012.04.013Search in Google Scholar PubMed

Ron, D. and Walter, P. (2007). Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529.10.1038/nrm2199Search in Google Scholar PubMed

Rowland, A.A. and Voeltz, G.K. (2012). Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat. Rev. Mol. Cell Biol. 13, 607–625.10.1038/nrm3440Search in Google Scholar PubMed PubMed Central

Schroder, M. and Kaufman, R.J. (2005). The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739–789.10.1146/annurev.biochem.73.011303.074134Search in Google Scholar PubMed

Shen, J., Chen, X., Hendershot, L., and Prywes, R. (2002). ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev. Cell 3, 99–111.10.1016/S1534-5807(02)00203-4Search in Google Scholar

Shen, W.W., Frieden, M., and Demaurex, N. (2011). Remodelling of the endoplasmic reticulum during store-operated calcium entry. Biol. Cell 103, 365–380.10.1042/BC20100152Search in Google Scholar PubMed

Stevens, F.J. and Argon, Y. (1999). Protein folding in the ER. Semin Cell Dev. Biol. 10, 443–454.10.1006/scdb.1999.0315Search in Google Scholar PubMed

Su, Q., Wang, S., Gao, H.Q., Kazemi, S., Harding, H.P., Ron, D., and Koromilas, A.E. (2008). Modulation of the eukaryotic initiation factor 2 -subunit kinase PERK by tyrosine phosphorylation. J. Biol. Chem. 283, 469–475.10.1074/jbc.M704612200Search in Google Scholar PubMed

Vacchelli, E., Ma, Y., Baracco, E.E., Sistigu, A., Enot, D.P., Pietrocola, F., Yang, H., Adjemian, S., Chaba, K., Semeraro, M., et al. (2015). Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. Science 350, 972–978.10.1126/science.aad0779Search in Google Scholar PubMed

van Vliet, A.R., Verfaillie, T., and Agostinis, P. (2014). New functions of mitochondria associated membranes in cellular signaling. Biochim. Biophys. Acta 1843, 2253–2262.10.1016/j.bbamcr.2014.03.009Search in Google Scholar PubMed

Vandenberk, L., Garg, A.D., Verschuere, T., Koks, C., Belmans, J., Beullens, M., Agostinis, P., De Vleeschouwer, S., and Van Gool, S. (2015). Irradiation of necrotic cancer cells employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma. Oncoimmunology, DOI:10.1080/2162402X.2015.1083669.Search in Google Scholar PubMed PubMed Central

Varnai, P., Hunyady, L., and Balla, T. (2009). STIM and Orai: the long-awaited constituents of store-operated calcium entry. Trends Pharmacol. Sci. 30, 118–128.10.1016/j.tips.2008.11.005Search in Google Scholar PubMed PubMed Central

Verfaillie, T., Rubio, N., Garg, A.D., Bultynck, G., Rizzuto, R., Decuypere, J.P., Piette, J., Linehan, C., Gupta, S., Samali, A., et al. (2012). PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ. 19, 1880–1891.10.1038/cdd.2012.74Search in Google Scholar PubMed PubMed Central

Verfaillie, T., Garg, A.D., and Agostinis, P. (2013). Targeting ER stress induced apoptosis and inflammation in cancer. Cancer Lett. 332, 249–264.10.1016/j.canlet.2010.07.016Search in Google Scholar PubMed

Vishnu, N., Jadoon Khan, M., Karsten, F., Groschner, L.N., Waldeck-Weiermair, M., Rost, R., Hallstrom, S., Imamura, H., Graier, W.F., and Malli, R. (2014). ATP increases within the lumen of the endoplasmic reticulum upon intracellular Ca2+ release. Mol. Biol. Cell. 25, 368–379.10.1091/mbc.e13-07-0433Search in Google Scholar PubMed PubMed Central

Wang, X.Z., Harding, H.P., Zhang, Y., Jolicoeur, E.M., Kuroda, M., and Ron, D. (1998). Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J. 17, 5708–5717.10.1093/emboj/17.19.5708Search in Google Scholar PubMed PubMed Central

Wang, R., McGrath, B.C., Kopp, R.F., Roe, M.W., Tang, X., Chen, G., and Cavener, D.R. (2013). Insulin secretion and Ca2+ dynamics in β-cells are regulated by PERK (EIF2AK3) in concert with calcineurin. J. Biol. Chem. 288, 33824–33836.10.1074/jbc.M113.503664Search in Google Scholar PubMed PubMed Central

Wu, M.M., Buchanan, J., Luik, R.M., and Lewis, R.S. (2006). Ca2+ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J. Cell Biol. 174, 803–813.10.1083/jcb.200604014Search in Google Scholar PubMed PubMed Central

Yamani, L., Latreille, M. and Larose, L. (2014). Interaction of Nck1 and PERK phosphorylated at Y(5)(6)(1) negatively modulates PERK activity and PERK regulation of pancreatic β-cell proinsulin content. Mol. Biol. Cell. 25, 702–711.10.1091/mbc.e13-09-0511Search in Google Scholar PubMed PubMed Central

Yamazaki, T., Hannani, D., Poirier-Colame, V., Ladoire, S., Locher, C., Sistigu, A., Prada, N., Adjemian, S., Catani, J.P., Freudenberg, M., et al. (2014). Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists. Cell Death Differ. 21, 69–78.10.1038/cdd.2013.72Search in Google Scholar PubMed PubMed Central

Zhou, R., Yazdi, A.S., Menu, P., and Tschopp, J. (2011). A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225.10.1038/nature09663Search in Google Scholar PubMed

Received: 2016-1-12
Accepted: 2016-2-8
Published Online: 2016-2-12
Published in Print: 2016-7-1

©2016 by De Gruyter

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Mitochondria, redox signaling and cell death in cancer
  4. HIGHLIGHT: EMBO WORKSHOP “MITOCHONDRIA, APOPTOSIS AND CANCER 2015”
  5. The anti-oxidant and pro-oxidant dichotomy of Bcl-2
  6. Mitosis and mitochondrial priming for apoptosis
  7. The role of Her2 and other oncogenes of the PI3K/AKT pathway in mitochondria
  8. Mechanisms of mitophagy: putting the powerhouse into the doghouse
  9. Controlling quality and amount of mitochondria by mitophagy: insights into the role of ubiquitination and deubiquitination
  10. Coordination of stress, Ca2+, and immunogenic signaling pathways by PERK at the endoplasmic reticulum
  11. Regulation of necroptosis signaling and cell death by reactive oxygen species
  12. Contrasting effects of cardiac glycosides on cisplatin- and etoposide-induced cell death
  13. iBH3: simple, fixable BH3 profiling to determine apoptotic priming in primary tissue by flow cytometry
  14. Review
  15. The impact of recent advances in genetics in understanding disease mechanisms underlying the long QT syndromes
https://doi.org/10.1515/hsz-2016-0108
Keywords for this article
calcium signaling; endoplasmic reticulum; immunogenic cell death; MAMs; mitochondria; PERK; plasma membrane; SOCE

Articles in the same Issue

  1. Frontmatter
  2. Guest Editorial
  3. Mitochondria, redox signaling and cell death in cancer
  4. HIGHLIGHT: EMBO WORKSHOP “MITOCHONDRIA, APOPTOSIS AND CANCER 2015”
  5. The anti-oxidant and pro-oxidant dichotomy of Bcl-2
  6. Mitosis and mitochondrial priming for apoptosis
  7. The role of Her2 and other oncogenes of the PI3K/AKT pathway in mitochondria
  8. Mechanisms of mitophagy: putting the powerhouse into the doghouse
  9. Controlling quality and amount of mitochondria by mitophagy: insights into the role of ubiquitination and deubiquitination
  10. Coordination of stress, Ca2+, and immunogenic signaling pathways by PERK at the endoplasmic reticulum
  11. Regulation of necroptosis signaling and cell death by reactive oxygen species
  12. Contrasting effects of cardiac glycosides on cisplatin- and etoposide-induced cell death
  13. iBH3: simple, fixable BH3 profiling to determine apoptotic priming in primary tissue by flow cytometry
  14. Review
  15. The impact of recent advances in genetics in understanding disease mechanisms underlying the long QT syndromes
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