BSCB PhD Award – Raff Medal Winner 2025: Pei Yee Tey

Raff PhD Medal Winner 2025

Pei Yee Tey

Born and raised in Malaysia, Pei Yee obtained her BSc in Biomedical Sciences from University College London (UCL), where she became fascinated by cell biology. For her MRes degree, she was trained at the LMCB under the supervision of Professor Mark Marsh and Dr Scott Lawrence, where she investigated how mutations in the envelope glycoprotein of the pathogenic simian immunodeficiency virus (SIV) influence envelope trafficking and virological synapse formation. She then relocated up north to join the Wellcome Trust PhD Programme in Cellular and Molecular Physiology at the University of Liverpool in 2019. Following a rotation year, she started her PhD in the labs of Professor Sylvie Urbé and Professor Michael Clague amid the COVID pandemic.

Pei Yee’s PhD research continued on the theme of membrane trafficking. Our understanding of receptor sorting and turnover mainly derives from studies on archetypal endocytic receptors, such as receptor tyrosine kinases. In comparison, work on the intracellular itinerary of immune checkpoint proteins is relatively sparse despite their prominence in the immune-therapeutic space. Ubiquitylation provides a critical signal to direct receptor sorting through the endo-lysosomal system and to mark proteins for degradation. Pei Yee was particularly keen to understand how ubiquitylation affects the stability and endo-lysosomal sorting of a highly dynamic immune checkpoint receptor, CTLA4. CTLA4 negatively regulates CD28-dependent T-cell signalling by interacting with and removing their shared ligands from antigen-presenting cells. Despite the need for cell surface appearance to bind its ligands, CTLA4 is mainly found in the intracellular compartments. Whilst ubiquitylation is known to mediate receptor trafficking, whether and if so, how ubiquitylation controls the intracellular sorting of CTLA4 was unclear.

Pei Yee showed that CTLA4 is an extremely short-lived membrane protein across cancer cell lines and that its lysosomal turnover relies on ubiquitylation at lysine residues 203 and 213. Using a candidate-based approach to deplete endosome-associated deubiquitylases (DUBs), she showed that the loss of USP8 upregulates CTLA4 ubiquitylation in cancer cell lines, mouse CD4-positive T cells and cancer cell-derived exosomes. Despite this increase in the degradative signal on CTLA4 upon USP8 depletion, CTLA4 turnover is delayed, most likely due to the overriding impacts on the downstream elements of the lysosomal degradation pathway. Inhibition of clathrin-dependent endocytosis slows CTLA4 degradation and abolishes its ubiquitylation signal in USP8-depleted cells, providing evidence that CTLA4 must pass through the plasma membrane before being internalised for degradation in a USP8-sensitive manner.

Once attached to a target protein, ubiquitin can be further modified and undergo ubiquitylation itself, forming eight distinct ubiquitin chain linkages (Met1, Lys6, Lys11, Lys27, Lys29, Lys33, Lys48 and Lys63). Of these chain linkages, the Lys63-linked chain is prominently linked to endocytosis. One of Pei Yee’s key findings is the surprising discovery that CTLA4 is associated with a composite ubiquitin chain profile. By performing a comprehensive ubiquitin chain restriction (UbiCRest) analysis, she uncovered that CTLA4 has a distinctive architecture of polyubiquitin chains composed of the well-characterised Lys63 and unconventional Lys27 and Lys29 linkages, which may underlie the rapidity of CTLA4 lysosomal turnover. Biological agents such as neutralising antibodies are currently used to target CTLA4 in clinics. Pei Yee’s work reveals the ubiquitin system as a fundamental player in CTLA4 biology. This opens up exciting new avenues for identifying druggable regulators of CTLA4 stability as an alternative CTLA4-targeting strategy.

Rapid lysosomal turnover of CTLA4 is associated with a complex architecture of reversible ubiquitylation. A balance of E3 ligase and deubiquitylating activity governs receptor fate at the endosome. Endosomal USP8 is proposed to recycle ubiquitin from CTLA4 prior, as well as after commitment to the lysosomal degradation pathway. Middle Panel: In the absence of USP8, a complex pattern of ubiquitylation accrues, composed of conventional Lys63 and unusual Lys27 and Lys29 ubiquitin linkages. This would normally lead to rapid degradation but is countermanded by downstream effects of USP8 loss that inhibit delivery to a degradative lysosome. Right Panel: Mutation of all lysine residues (K-null) or just the critical two lysine residues (K203 and K213) to arginine residues in the cytoplasmic tail of CTLA4 interferes with endolysosomal sorting and downregulation. These CTLA4 mutants accumulate in early (sorting) endosomes and fail to progress to later endolysosomal compartments. For reasons of clarity, mono-ubiquitylation, branching and diversity of chain length are not depicted. ©2025 TEY et al. Originally published in the Journal of Cell Biology. https://doi.org/10.1083/jcb.202312141

During her PhD, Pei Yee communicated her research at national and international conferences, where she was awarded best poster and best short talk prizes on different occasions. Her work has recently been published in the Journal of Cell Biology (https://doi.org/10.1083/jcb.202312141). Pei Yee is currently working as a postdoc in the Urbé/Clague lab, where she continues to dissect the ubiquitin-dependent turnover of CTLA4. Outside of work, she enjoys experimenting in her patisserie lab.

You can follow Pei Yee on LinkedIn, Bluesky (@imPeiYee.bsky.social) and X (@imPeiYee).

Pei Yee will be awarded the Raff Medal and give a talk about her research during the Biologists @ 100 conference which is being held jointly between BSCB and The company of Biologists on 24-27 March 2025 at ACC Liverpool, UK.

The BSCB PhD Award – Raff Medal was established in 2020  to recognise BSCB PhD students who have made outstanding contributions to UK/Ireland cell biology. The medal has been named after Professor Martin Raff who was the president of BSCB from 1992-1995. Martin was instrumental in setting up and running the first 4-year PhD graduate programme in Molecular Cell Biology at the MRC Laboratory for Molecular Cell Biology (LMCB) at UCL.