One of the most important challenges facing biomedical research is to understand the molecular details of how our immune system defends against pathogens. In the Swatek lab, we aim to understand the roles of ubiquitin and ubiquitin-like modifications in the antiviral state (1). These modifications have emerged as crucial mediators of the signal transduction pathways that sense and respond to viruses. The ubiquitin-like protein, ISG15, is highly upregulated during the antiviral state and marks thousands of proteins to help shape the host defence response. To subvert ISG15 signalling, many viruses encode enzymes that remove these modifications, and we have previously identified an elegant example of viral ISG15 suppression (2). Surprisingly, however, the roles of the vast majority of ISG15 modifications are unknown, and therefore, understanding how ISG15 contributes to the antiviral state is of paramount importance. This PhD project aims to identify novel substrates and pathways regulated by ISG15 signalling and link these discoveries to a cellular function.

This project takes advantage of our expansive toolkit to study the ISG15 system. Students interested in gaining expertise in a wide variety of approaches are strongly encouraged to apply since the project merges several disciplines, including method development, state-of-the-art mass spectrometry, cell biology, structural biology, biophysics, and biochemistry (3-4). The student will have a unique opportunity to work at the bench alongside their supervisor and the opportunity to participate in several internal and external collaborations.

1. Swatek KN, and Komander D (2016). Ubiquitin modifications. Cell Research. Vol. 26, 399-422.
2. Swatek KN, Aumayr M, Pruneda JN, Visser L, Berryman S, Kueck A, Kuppeveld FV, Tuthill T, and Komander D (2018). Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies. PNAS. Vol. 115, 2371-2376.
3. Swatek KN, Usher JL, Kueck AF, Gladkova C, Mevissen TET, Pruneda JN, Skern T, and Komander D (2019). Insights into ubiquitin chain architecture using Ub-clipping. Nature. Vol. 572, 533-537.
4. Wallace I, Baek K, Prabu JR, Vollrath R, Gronau SV, Schulman BA, and Swatek KN (2023). Insights into the ISG15 transfer cascade by the UBE1L activating enzyme. Nature Communications. Vol. 14, 1-13.