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.
Preissler S, Rato C, Chen R, Antrobus R, Ding S, Fearnley IM & Ron D. Ampylation matches bip activity to client protein load in the endoplasmic reticulum. eLife 4: 10.7554/eLife.12621 (2015). (PMID: 26673894).
Preissler S, Chambers JE, Crespillo-Casado A, Avezov E, Miranda E, Perez J, Hendershot LM, Harding HP & Ron D. Physiological modulation of BiP activity by trans-protomer engagement of the interdomain linker. eLife 4: 10.7554/eLife.08961 (2015). (PMID: 26473973).
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 (10.1126/science.aaa6986) (PMID: 25858979)
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)
Chambers JE, Dalton LE, Clarke HJ, Malzer E, Dominicus CS, Patel V, Moorhead G, Ron D and Marciniak SJ. 2015. Actin dynamics tune the integrated stress response by regulatins eukaryotic initiation factor 2α dephosphorylation. eLIFE 4:(10.7554/eLife.04872) (PMID: 25774599)
Avezov E, Konno T, Zyryanova A, Chen W, Laine R, Crespillo-Casado A, Pinho Melo E, Ushioda R, Nagata K, Kaminski C, Harding HP and Ron D. 2015. Retarded PDI diffusion and a reductive shift in poise of the calcium depleted endoplasmic reticulum. BMC Biology DOI:10.1186/s12915-014-0112-2 (PMID: 25575667)
Tsunoda S, Avezov E, Zyryanova A, Konno T, Mendes-Silva L, Pinho Melo E, Harding HP, and Ron D. 2014. Intact protein folding in the glutathione-depleted endoplasmic reticulum implicates alternative protein thiol reductants. eLIFE DOI: 10.7554/eLife.03421 (PMID: 25073928)
Avezov E, Cross BC, Kaminski Schierle GS, Winters M, Harding HP, Melo EP, Kaminski CF and Ron D. 2013. Lifetime imaging of a fluorescent protein sensor reveals surprising stability of er thiol redox. J. Cell Biol. 201:337-49 (PMID: 23589496)
Volmer R, van der Ploeg K and Ron D. 2013. Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc. Natl. Acad. Sci. U. S. A. 2013 110:4628-33. doi: 10.1073/pnas.1217611110. Epub 2013 Mar 4 (PMID: 23487760). Highlighted in Science Magazine Editor's Choice and by a citation in Faculty of 1000
Harding HP, Zyryanova AF and Ron D. 2012. Uncoupling proteostasis and development in vitro with a small molecule inhibitor of the pancreatic endoplasmic reticulum kinase, PERK. J. Biol. Chem. 287:44338-44 (PMID: 23148209) (access to online version on publisher's website). Note: the compound described in the paper is now available commercially from Millipore Calbiochem (Cat. 516535).
Zito E, Hansen H, Yeo G, Fujii J and Ron D. 2012. Endoplasmic reticulum thiol oxidase deficiency leads to ascorbic acid depletion and non-canonical scurvy in mice. Mol. Cell 48:39-51 (PMID: 22981861) (access to final version on publisher's website)
Chambers JE, Petrova K, Tomba G, Vendruscolo M and Ron D. 2012. ADP ribosylation adapts an ER chaperone response to short-term fluctuations in unfolded protein load. J. Cell Biol. 198:371-85 (PMID: 22869598). Also see commentary by Pincus and Walter in: J. Cell Biol. 198:277-9 (PMID: 22869593) and citation in Faculty of 1000
A full list of publications can be found on the Ron lab homepage.