Dr Richard Timms; CITIID, Department of Medicine, University of Cambridge
Richard recently started his independent laboratory at the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)on the Cambridge Biomedical Campus. The goal of his work is to develop and exploit genetic tools to understand how the ubiquitin-proteasome system achieves selective protein degradation. Richard’s interest in genetics began as a Ph.D student with Prof. Paul Lehner at the Cambridge Institute of Medical Research, where he developed genetic screens in haploid human cells to study viral E3ubiquitin ligases. He then moved to Boston as a Sir Henry Wellcome Postdoctoral Fellow working in the lab of Prof. Steve Elledge at Harvard Medical School. There he discovered novel degradative pathways through which Cullin-RING E3 ligases target their substrates via degrons located at extreme N- and C-termini. The expression screening techniques he developed to interrogate E3 ligase-substrate interactions form the basis of work in his new lab.
Adaptation to fluctuating nutrient supply is essential for organismal survival, but how cells sense and respond to changes in the abundance of many amino acids remains undefined. Although rapid alteration to protein function via phosphorylation is central to the amino acid-sensing pathways defined thus far, a role for ubiquitin in conditional protein degradation remains underexplored. In search of the machinery required for the conditional degradation of cysteine dioxygenase type I (CDO1), the critical enzyme responsible for cysteine catabolism, we have uncovered a Cul2 E3 ligase complex containing the uncharacterized substrate adaptor LRRC58 that is sensitive to cysteine abundance. I will describe our ongoing work to characterise how cysteine levels control the LRRC58-mediateddegradation of CDO1 and discuss the physiological consequences resulting from the genetic mutations which disrupt the CDO1-LRRC58 homeostatic axis.
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