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Cambridge Immunology Network



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.


Other publications: 

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

Other Professional Activities

Public Involvement/Engagement


Professor Marciniak is a member of CIMR’s public engagement committee.



  • September 2019: Talked to students in Y10 from Newmarket Academy who were undertaking guided research in St Catharine’s College.
  • November 2019: Talked to Y12s from Lowestoft Sixth Form. 
  • Online lecture on behalf of the Sutton Trust (a charity which aims to increase university applications from individuals from disadvantaged backgrounds). 
  • Professor Marciniak and Professor Morrell gave an online “fireside chat” streamed on the St Catharine’s College YouTube channel and now available online [link]. They discussed the medical response to COVID-19 by members of the University and how it has affected students.
  • 28 November 2020: Talk at RAREfest20 this year being run as a virtual public engagement event for >700 patients and families.  
  • 30 November 2020: Talk at Mesothelioma UK online event on their research using nanotechnology to kill mesothelioma cancer cells.
  • 27 March 2021: Presentation for the Cambridge Science Festival, on behalf of the CIMR and Alliance Française.

News media

  • “Fellow finds punctured lung affects one in a hundred hospitalised COVID-19 patients” [link to college page, includes links to articles in the Telegraph, Metro, Independent, Evening Standard, Forbes and several local papers]
  • “Using gold nanotubes to kill mesothelioma cells” [link to college page, which has links to Daily Mail, BBC Science Focus and several other news sites]. Longer news feature planned by the BBC at CIMR.
Professor  Stefan  Marciniak
Not available for consultancy


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