Research at LICR Oxford Dr John Christianson

Research Overview

 

Approximately one third of the human genome codes for proteins that traffic through the secretory pathway. More than a mere conduit, this series of organelles regulates protein flux while at the same time ensuring the highest level of fidelity for its transiting protein load. Genetic mutations, post-transcriptional errors, destabilized domains or a missing post-translational modification/binding partner can all give rise to non-functional and orphan translation products, whose unabated accumulation or exposure to the extracellular environment can negatively impact cellular homeostasis and viability. To prevent this from occurring, the endoplasmic reticulum (ER) harbors two intrinsic and integrated quality control mechanisms, 1) chaperone-assisted protein folding and 2) ER-associated degradation (ERAD).

 

My lab’s principal focus is on ERAD, the multifaceted process that 1) recognizes deleterious substrates, 2) retrotranslocates them across the ER membrane, and 3) ultimately degrades them by the ubiquitin-proteasome system (UPS). More than 40 unique proteins have been implicated in ERAD, many as part of transiently forming macromolecular complexes. ERAD genes are transcriptionally regulated by ER stress and are an integral facet of the unfolded protein response (UPR). ERAD also plays a central role in a number of inherited disorders including cystic fibrosis and α 1-antitrypsin disease. Additionally, there is recent evidence suggesting that ERAD plays a key role in regulating tumor suppressor protein levels and separate studies have linked ERAD genes to various forms of cancer.

 

Our interests lie in characterizing essential components of the ERAD mechanism and indentifying novel substrates of this pathway. We employ proteomic, cell biological and biochemical techniques to identify factors, characterize the complexes they function in, and understand the substrate-specificity with which they operate. We are keenly interested in understanding the role that quality control at the level of the ER plays in the expression of proteins responsible for tumor progression and metastasis. Our long term goals are to explore quality control mechanisms as a novel point of intervention for cancer therapies.

 

 

Key Publications

 

Christianson, J.C., Shaler, T.A., Tyler, R.E. and Kopito, R.R. (2008) GRP94 and OS-9 deliver mutant α1-antitrypsin to the SEL1L-Hrd1 ubiquitin ligase complex for ERAD. Nature Cell Biology 10: 272-282.

 

DeLaBarre, B.S.*, Christianson, J.C.*, Kopito R.R, Brunger, A.T. (2006) Central Pore Residues Mediate the p97/VCP Activity Required for ERAD. Molecular Cell 22(4):451-62. (*equal authorship)

 

Iwata, A., Christianson, J.C., Bucci, M., Ellerby, L.M., Nukina, N., Forno, L.S. and Kopito R.R. (2005) Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. P.N.A.S. 102 (37):13135-40.

Christianson, J.C. and Green W.N. (2004) Regulation of nicotinic receptor expression by the ubiquitin-proteasome system. EMBO J. 23(21): 4256-65.