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David Ron

Protein folding homeostasis in the endoplasmic reticulum

Proteins that fail to attain or maintain their structure reduce fitness in part through toxic gain of function mechanisms referred to as "proteotoxicity". The latter conspicuously affects poorly-renewable tissues of long-lived organisms in which the threat of protein misfolding can exert its deleterious consequences over extended periods of time. Protein misfolding is compartment-specific and its extent is influenced by the burden of newly-synthesized unfolded proteins presented to given compartment (cytosol, endoplasmic reticulum, mitochondria) and by the protein folding environment in that compartment. The latter is influenced by structural elements operating within and on the compartment and by its metabolic state. Both parameters are regulated by complex homeostatic pathways, constituting a proteostasis network in which compartment-specific unfolded protein responses (UPR) are important.

Interesting reciprocal links have been uncovered between protein folding homeostasis and metabolism: Defects in handling unfolded protein load and proteotoxic features of rare mutant proteins have revealed the importance of proteostasis to the function of tissues such as the endocrine pancreas, liver and fat that figure heavily in metabolic control. Less well understood, but of potentially considerable importance, are the emerging links between intermediary metabolism and the protein folding environment in the various compartments of the eukaryotic cell. Working with colleagues at the Cambridge Institute for Medical Research, we hope to understand the molecular basis of the aforementioned reciprocal links and thereby uncover informative clinical markers and targets for future therapeutic interventions.

Ron lab homepage

 Ron lab 2016

Key papers:

Perera LA, Rato C, Yan Y, Neidhardt L, McLaughlin SH, Read RJ, Preissler S and Ron D. 2019. An oligomeric state-dependent switch in the ER enzyme FICD regulates AMPylation and deAMPylation of BiP. EMBO J.:e102177 (10.15252/embj.2019102177) (PMID: 31531998)

Zyryanova AF, Weis F, Faille A, Alard AA, Crespillo-Casado A, Sekine Y, Harding HP, Allen F, Parts L, Fromont C, Fischer PM, Warren AJ and Ron D. 2018. Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science 359:1533-6 (PMID: 29599245)

Amin-Wetzel N, Saunders RA, Kamphuis MJ, Rato C, Preissler S, Harding HP and Ron D. 2017. A J-protein co-chaperone recruits BiP to monomerize IRE1 and repress the unfolded protein response. Cell 171:1625-37 (10.1016/j.cell.2017.10.040) (PMID: 29198525)

Preissler S, Rohland L, Yan Y, Chen R, Read RJ and Ron D. 2017. AMPylation targets the rate-limiting step of BiP’s ATPase cycle for its functional inactivation. ELife 6:e29428 (PMID: 29064368)

Kono N, Amin-Wetzel N and Ron D. 2017. Generic membrane spanning features endow IRE1a with responsiveness to membrane aberrancy. Mol. Biol. Cell 28:2318-32 (10.1091/mbc.E17-03-0144) (PMID: 28615323)

Crespillo-Casado A, Chambers JE, Fischer PM, Marciniak SJ and Ron D. 2017. Ppp1r15a-mediated dephosphorylation of eif2a is unaffected by sephin1 or guanabenz. Elife 6:e26109 (PMID: 28447936)

Preissler S, Rato C, Perera LA, Saudek V and Ron D. 2017. FICD acts bifunctionally to AMPylate and de-AMPylate the endoplasmic reticulum chaperone BiP. Nature Struct. Mol. Biol. 24:23-9 (10.1038/nsmb.3337) (PMID: 27918543)

Preissler S, Rato C, Chen R, Antrobus R, Ding S, Fearnley IM and Ron D. 2015. AMPylation matches BiP activity to client protein load in the endoplasmic reticulum. eLife 4:(10.7554/eLife.12621) (PMID: 26673894)

Sekine Y, Zyryanova A, Crespillo-Casado A, Fischer PM, Harding HP and Ron D. 2015. Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science 348:1027-1030(10.1126/science.aaa6986) (PMID: 25858979). See perspective article by Alan Hinnebusch.

Chen R, Rato C, Yan Y, Crespillo-Casado A, Clarke HJ, Harding HP, Marciniak SJ, Read RJ and Ron D. 2015. G-actin provides substrate-specificity to eukaryotic initiation factor 2a holophosphatase. eLife 4:(10.7554/eLife.04871) (PMID: 25774600)

A full list of publications can be found on the Ron lab homepage.

David Ron

David Ron

Professor of Cellular Pathophysiology and Clinical Biochemistry, FRS

Wellcome Trust Principal Research Fellow

Department: Clinical Biochemistry


01223 768 940

Plain English

Proteins must fold into their correct three-dimensional structure to function properly and cells are adept at detecting and responding to incorrect protein folding. Secreted proteins and membrane proteins — which are often of medical importance — fold in a particular compartment, the endoplasmic reticulum, where misfolded proteins trigger an 'unfolded protein response' that contributes to their extraction and destruction. Our research focuses on the control of this process and the implications of this for protein folding diseases and ageing. We are also investigating emerging connections between the regulation of protein folding and metabolism in the pancreas, liver and fat. Our hope is that better understanding of protein folding and surveillance might provide opportunities for new therapies.

Group members

Heather P. Harding · Lisa Neidhardt · Adriana Ordonez · Luke Perera · Steffen Preissler · Luka Smalinskaite · Yahui Yan · Alisa Zyryanova



Wellcome Trust