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Stefan Marciniak

The role of endoplasmic reticulum stress in disease

Studying the consequences of protein misfolding in the endoplasmic reticulum (ER), termed ER stress, particularly on cell growth and survival.

Proteins destined for secretion or for insertion into the cell membrane are first folded within the endoplasmic reticulum. The process of protein folding can become defective in many disease states such as hypoxia, malignancy and some forms of diabetes. When the level of misfolded proteins within the endoplasmic reticulum increases, the cell is said to experience 'endoplasmic reticulum stress'.

We wish to understand the cellular consequences of endoplasmic reticulum stress, in particular its effects on tissue growth and cell survival. In doing so, we hope to identify targets for the development of novel therapies. During endoplasmic reticulum stress, protein biosynthesis is initially attenuated through phosphorylation of the translation initiation factor eIF2α by the kinase PERK.  Subsequent dephosphorylation of eIF2α following the induction of the phosphatase PPP1R15a (GADD34) restores protein translation. We previously discovered that this recovery of translation can contribute to the toxic effects of endoplasmic reticulum stress. This raises the exciting possibility that modulation of eIF2α phosphorylation may provide a useful target for the development of novel drugs to protect tissues from cell death.

Drosophila imaginal disc

Cellular stresses frequently impair cell cycle progression, which can prejudice tissue growth. Using mammalian cell biology and Drosophila genetics we recently described a novel G2 cell cycle checkpoint initiated by translation attenuation during endoplasmic reticulum stress. This too provides potential targets for the development of new therapies.


This movie shows CHO cell expressing YFP-Z-α1-antitrypsin subjected to serial blockface scanning electron microscopy. The surface of antitrypsin-containing inclusions were traced in 2D images and combined to generate a 3D projection by isosurface rendering with a surface area detail of 36nm. Distinct coloration of physically separated inclusions showed that many of these structures contacted one another, but inspection of the original 3View stack revealed that inclusion membrane contacts were almost never accompanied by evidence of inter-luminal connectivity.

Marciniak lab 2016

Key papers:

Patel V, Bidault G, Chambers JE, Carobbio S, Everden AJT, Garcés C, Dalton LE, Gribble FM, Vidal-Puig A3, Marciniak SJ. Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in female mice. Scientific Reports. Feb 27;9(1):2903 (2019)
doi: 10.1038/s41598-019-39562-y

Chambers JE, Dickens JA, Marciniak SJ.  Measuring the effects of α1 -antitrypsin polymerisation on the structure and biophysical properties of the endoplasmic reticulum Biology of the Cell Nov;110(11):249-255 (2018).
doi: 10.1111/boc.201800023. Epub  Sep 10 2018.

Chambers JE, Kubankova M, Huber R, López-Duart I, Avezov E, Bond P, Marciniak SJ* & Kuimova M*.  An optical technique for mapping microviscosity dynamics in cellular organelles. ACS Nano. May 22;12(5):4398-4407 (2018) *Joint senior authors
doi: 10.1021/acsnano.8b00177

Malzer E, Dominicus CS, Chambers JE, Dickens JA, Mookerjee S & Marciniak SJ. The integrated stress response regulates BMP signaling through effects on translation.  BMC Biology 16:34 (2018)

Holcman D, Parutto P, Chambers JE, Fantham M, Young LJ, Marciniak SJ, Kaminski CF, Ron D, Avezov E. Single particle trajectories reveal active endoplasmic reticulum luminal flow. Nature Cell Biology Oct;20(10):1118-1125 (2018).
doi: 10.1038/s41556-018-0192-2. Epub 2018 Sep 17.

Segeritz CP, Rashid ST, de Brito MC, Serra MP, Ordonez A, Morell CM, Kaserman JE, Madrigal P, Hannan NRF, Gatto L, Tan L, Wilson AA, Lilley K, Marciniak SJ, Gooptu B, Lomas DA, Vallier L. hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency. J Hepatol. Oct;69(4):851-860 (2018)
doi: 10.1016/j.jhep.2018.05.028. Epub 2018 Jun 5.

Scott RM, Henske EP, Raby B, Boone PM, Rusk RA & Marciniak SJ. Familial pneumothorax – towards precision medicine. Thorax 73:270-276 (2018).

Dickens JA, Ordóñez A, Chambers JE, Beckett AJ, Patel V, Malzer E, Dominicus CS, Bradley J, Peden AA, Prior IA, Lomas DA & Marciniak SJ.  The endoplasmic reticulum remains functionally connected by vesicular transport after its fragmentation in cells expressing Z-α1-antitrypsin.  FASEB J. 30: 4083-4097 (2016).

van‘t WoutEFA, van Schadewijk A, van Boxtel R, Dalton LE, Clarke HJ, Tommassen J, Marciniak SJ* & Hiemstra PS*. Virulence factors of Pseudomonas aeruginosa induce both the unfolded protein and integrated stress responses in airway epithelial cells.  PLoS Pathogens 11(6): e1004946 (2015). *Joint senior authors

Chambers JE, Dalton LE, Clarke HJ, Malzer E, Dominicus CS, Patel V, Moorhead G, Ron D, Marciniak SJ. Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation. Elife 4, doi: 10.7554/eLife.04872 (2015).

Chen R, Rato C, Yan Y, Crespillo-Casado A, Clarke HJ, Harding HP, Marciniak SJ*, Read RJ*, Ron D*. G-actin provides substrate-specificity to eukaryotic initiation factor 2α holophosphatases. Elife 4, doi: 10.7554/eLife.04871 (2015). *Joint corresponding authors.

van ‘t Wout, E.F.A., Dickens, J.A., van Schadewijk, A., Haq, I., Kwok, H.F., Ordóñez, A., Murphy, G., Stolk, J., Lomas, D.A., Hiemstra, P.S. and Marciniak, S.J. Increased ERK signalling promotes inflammatory signalling in primary airway epithelium expressing Z α1-antitrypsin.  Hum. Mol. Gen. 23, 929–941 (2014).

Malzer, E, Szajewska-Skuta, M., Dalton, L.E., Thomas, S.E., Hu, N., Skaer, H., Lomas, D.A., Crowther, D.C., and Marciniak, S.J. Coordinate regulation of eIF2α phosphorylation by dPPP1R15 and dGCN2 is required during Drosophila development.  J. Cell Sci. 126, 1406–1415 (2013).

Ordóñez, A., Snapp, E.L., Tan, L., Miranda, E., Marciniak, S.J.§* and Lomas, D.A.* Endoplasmic reticulum polymers impair luminal protein mobility and sensitise to cellular stress in α1-antitrypsin deficiency. Hepatology 57, 2049–2060 (2013). *Joint senior authors §Corresponding author

Stefan Marciniak

Professor Stefan Marciniak

Professor of Respiratory Science

Department: Medicine


01223 762660


Plain English

Proteins must be folded properly to function. If this becomes defective, cells experience stress and respond by clearing away these misfolded proteins for destruction. We are interested in the control of this stress response and its importance during development, cell growth and death. We focus on both mammals and fly models with the aim of understanding how this pathway is regulated in different animals and might be targeted to prevent unwanted cell death in disease.

Group members

Arsalan Azad · Joe Chambers · Jenny Dickens · Giulia Emanuelli · Joanna Obacz · Susana Rodrigues de Abreu · Eimear Rutherford · Max Schwiening · Marie Shamseddin (visiting researcher) · Elaine Soon · Haoyang Ying · Nikita Zubkov


Medical Research Council

British Lung Foundation

Alpha-1 Foundation