Targeted Protein Degradation
Groups Bachmair Becker Beli Clausen Dagdas Haselbach Karagöz Köhler Loizou (former member) Martens Urbán Versteeg Winter

Group Versteeg

Degradation mechanisms of antiviral APOBEC proteins

Group Leader

Gijs Versteeg

Gus Versteeg started his independent research group at the Max Perutz Labs Vienna in 2013. His previous work explored how ubiquitination mediates immune system activation. His group currently investigates how the abundance of immune- and cancer-related proteins is controlled by proteasomal degradation.

Projects within consortium

APOBEC proteins are essential host-defense factors that act by hyper-mutating viral genetic material. However, some APOBEC proteins have been shown to aberrantly target host cell DNA, contributing to hyper-mutation signatures in certain cancers. The aim of this project is to identify new cellular factors ensuring that these factors do not mutate their own DNA, and unravel how they do so at a mechanistic molecular level.

Members of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family of cytosine deaminases are important viral restriction factors, preventing HIV species barrier crossing. In contrast to these host-beneficial properties, recent analyses indicate that some of the different APOBEC3 family member can have detrimental effects in humans by driving cellular hyper-mutation in breast and lung cancers, thereby contributing to a broader, disadvantageous mutational landscape within these tumors.

Current data indicate that there is a yet unidentified nuclear degradation pathway limiting APOBEC accumulation in the nucleus, thereby limiting exposure of the DNA to the mutagenic action of the APOBEC3 protein. We hypothesize that efficient degradation of nuclear APOBEC3 proteins is important to prevent genotoxicity, and hence genome integrity.

This project aims to identify the key players in nuclear APOBEC3 degradation, and understand key mechanistic steps of APOBEC3 ubiquitination and proteasomal degradation using genetic screening platforms, as well as cellular and biochemical assays.

Taken together, results from this project will provide insight into nuclear control mechanisms ensuring genome stability, and how deregulation of this pathway may contribute to cancer progression.

APOBEC3 proteins are essential antiviral hyper-mutators. This project aims to identify factors degrading nuclear APOBEC3, thereby preventing host genome mutagenesis.

Project members

  • PhD Student

    Irene Schwartz

    SFB Member

  • PhD Student

    Alexandra Shulkina

    SFB Member

  • PhD Student

    Valentina Budroni

    Associated

Targeted Protein Degradation related publications by Group Versteeg

  • 2023 SPOP targets the immune transcription factor IRF1 for proteasomal degradation eLife Schwartz I, Vunjak M, Budroni V, Cantoran García A, Mastrovito M, Soderholm A, Hinterndorfer M, de Almeida M, Hacker K, Wang J, Froussios K, Jude J, Decker T, Zuber J, Versteeg GA. Go to publication →
  • 2023 Stress-induced clustering of the UPR sensor IRE1α is driven by disordered regions within its ER lumenal domain bioRxiv Kettel P, Marosits L, Spinetti E, Rechberger M, Radler P, Niedermoser I, Fischer I, Versteeg GA, Loose M, Covino R, Karagöz GE Go to publication →
  • 2023 HUWE1 controls tristetraprolin proteasomal degradation by regulating its phosphorylation eLife Scinicariello S, Söderholm A, Schäfer M, Shulkina A, Schwartz I, Hacker K, Gogova R, Kalis RW, Froussios K, Budroni V, Bestehorn A, Clausen T, Kovarik P, Zuber J, Versteeg GA. Go to publication →
  • 2023 Structural basis of how the BIRC6/SMAC complex regulates apoptosis and autophagy Science Ehrmann JF, Grabarczyk DB, Heinke M, Deszcz L, Kurzbauer R, Hudecz O, Shulkina A, Gogova R, Meinhart A, Versteeg GA, Clausen T Go to publication →
  • 2021 AKIRIN2 controls the nuclear import of proteasomes in vertebrates Nature de Almeida M, Hinterndorfer M, Brunner H, Grishkovskaya I, Singh K, Schleiffer A, Jude J, Deswal S, Kalis R, Vunjak M, Lendl T, Imre R, Roitinger E, Neumann T, Kandolf S, Schutzbier M, Mechtler K, Versteeg GA, Haselbach D, Zuber J Go to publication →
  • 2019 A repetitive acidic region contributes to the extremely rapid degradation of the cell-context essential protein TRIM52 Scientific Reports Hacker K, Benke S, Agerer B, Scinicariello S, Budroni V, Versteeg GA Go to publication →
  • 2018 Human tripartite motif protein 52 is required for cell context-dependent proliferation Oncotarget Benke S, Agerer B, Haas L, Stöger M, Lercher A, Gabler L, Kiss I, Scinicariello S, Berger W, Bergthaler A, Obenauf AC, Versteeg GA Go to publication →