Dr David Komander - Ubiquitin Signalling division

Dr David Komander - Ubiquitin Signalling division

Location: 
Davis Auditorium
Start Time: 
Wed, 27/02/2019 - 1:00pm
End Time: 
Wed, 27/02/2019 - 2:00pm

 

Deubiquitinases: Opportunities, observations and open questions

 

​Wednesday seminar

Ubiquitination regulates a myriad of cellular process, most prominently protein stability. Deubiquitinases (DUBs) remove ubiquitin, and regulate ubiquitin signalling. Some DUBs are endowed with remarkable linkage-specificity, which enables  detailed insights into the roles of the ubiquitin signal. OTULIN is a DUB specific for M1-linked ´linear´ ubiquitin chains, and regulates inflammation, infection, and immunity. Mutations in the gene lead to OTULIN related autoinhibitory syndrome (ORAS), a human monogenic disease. A new patient case has recently enabled fresh insights into roles of OTULIN in cell death, and new treatment options. In addition, it is emerging that OTULIN, and potentially linear ubiquitin chains, regulate signalling processes outside inflammation.

Most DUBs stabilise proteins – inhibition of a cognate DUB hence enables destabilisation of any protein including ‘undruggables’, which has generated some excitement in the pharmaceutical industry. The results from multiple academic and industrial efforts are emerging in the literature, and the data show that DUBs are druggable with specific, high affinity small molecules. The Komander lab was part of the DUB Alliance, a CRUK-led academic-industrial partnership set up to identify DUB inhibitors, and some results from these works will be presented. This part of the talk  will focus on USP28 which regulates c-MYC and other oncogenes, and it’s close paralogue USP25 that has been linked to TRAF3 signalling.

The talk will also include an overview of the questions and technologies to be established, in the new Ubiquitin Signalling division.