skip to primary navigationskip to content

Dr James Nathan

Research Interests

I am interested in the role of the ubiquitin proteasome system (USP) in the regulation of protein degradation and inflammation. Ubiquitination is an essential post-translational modification that regulates diverse cellular pathways, ranging from degradation and endocytosis to signalling and cell cycle control. Any disruption of ubiquitination has the potential to lead to dysregulation of cellular homeostasis, thereby leading to cancer and inflammation (e.g. disruption of NF-kB or HIF1a signalling) or the accumulation of damaged proteins, such as those that aggregate in neurodegenerative conditions. Using a combination of genetic, biochemical and cell biology approaches my goals are to understand how ubiquitinated proteins are targeted for degradation.


Ubiquitin Binding Proteins determine the fate of ubiquitinated proteins.


Complexity in the UPS results from the ability of ubiquitin to form up to eight different polyubiquitin chains by covalent linkage through one of its seven lysine residues, or through its N-terminus (linear chains). The importance of these different chain linkages are exemplified by their role in inflammation signalling pathways, such as NF-kB signalling, where each type of ubiquitin linkage serves distinct functions. We have shown that chain-specific ubiquitin binding proteins (UBPs) are critical for determining the cellular fate of the ubiquitinated protein.  Using biochemical and cell biology approaches we have shown that lysine-48 (K48) chain-specific UBPs bind strongly K48-ubiquitinated proteins, stimulating and facilitating proteasomal degradation, whereas K63-specific UBPs prevent K63-ubiquitinated proteins from binding to the proteasome, and alternatively deliver them to the endosomal-lysosomal system.

Mechanisms of protein degradation by different proteasome species following inflammation.

The immunoproteasome is a specialized form of the 26S proteasome that is required for the efficient generation of peptides, which are subsequently loaded onto MHC Class I molecules. Whether immunoproteasomes have an increased capacity to degrade ubiquitin conjugates was controversial. We have shown that constitutive and immunoproteasomes degrade ubiquitin conjugates at similar rates, and demonstrated for the first time the kinetics of degradation of these two proteasome species.

Key Publications

Nathan J.A., Spinnenhirn V, Schmidtke G, Basler M, Groettrup M and Goldberg A.L. (2013). Immuno- and constitutive proteasomes do not differ in their ability to degrade ubiquitinated proteins. Cell 152, 1184-94.

Nathan J.A., Kim HT, Ting L, Gygi S, and Goldberg A.L. (2013). Why do cell proteins linked to K63-polyubiquitin chains not associate with proteasomes? EMBO J 32, 552-65.

Deriziotis, P., Andre, R., Smith, D.M., Goold, R., Kinghorn, K.J., Kristiansen, M., Nathan, J.A., Rosenzweig, R., Krutauz, D et al (2011). Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry. EMBO J, Jul 8;30(15):3065-77.

Duncan, L.M., Nathan, J.A., and Lehner, P.J. (2010). Stabilization of an E3 ligase- E2-ubiquitin complex increases cell surface MHC class I expression. J Immunol 184, 6978-6985.

Nathan, J.A., and Lehner, P.J. (2009). The trafficking and regulation of membrane receptors by the RING-CH ubiquitin E3 ligases. Exp Cell Res 315, 1593-1600.

Nathan, J.A., Sengupta, S., Wood, S.A., Admon, A., Markson, G., Sanderson, C., and Lehner, P.J. (2008). The ubiquitin E3 ligase MARCH7 is differentially regulated by the deubiquitylating enzymes USP7 and USP9X. Traffic 9, 1130- 1145.