Universität zu Köln

Profe-Austermann, Friederike ORCID: 0009-0005-4202-5921 (2026). SUMO and SUMO-targeted Ubiquitin Ligases in Protein Quality Control. PhD thesis, Universität zu Köln.

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Abstract

The small ubiquitin-like modifier (SUMO) is a posttranslational modification involved in various cellular processes, such as the regulation of the cell cycle and genome stability. Through so-called SUMO-targeted Ubiquitin ligases (STUbLs), SUMOylation can also lead to the degradation of proteins. STUbLs recognize SUMO chains via their SUMO-interacting motifs (SIMs) and recruit ubiquitin conjugating enzymes using their RING domain. This leads to the ubiquitylation of the SUMO chain and subsequent targeting of the substrate for proteasomal degradation. One STUbL system in S. cerevisiae is the heterodimer Slx5-Slx8 (Uls2), which has predominantly been described in the targeting of nuclear proteins involved in DNA-related processes. In this study, it was shown that Uls2 is part of a quality control mechanism for cytosolic proteins. In this thesis, the working hypothesis was developed that, upon stress or absence of an interaction partner, a hidden SIM or SUMOylation site of a protein is exposed triggering its polySUMOylation. PolySUMOylation of the protein then leads to nuclear localization and subsequent targeting for degradation through Uls2. In light of this hypothesis, it was shown that two proteins - Nis1 and Fir1 – are targeted by Uls2 upon their overexpression. Both proteins are targeted to the nucleus upon overexpression, where they accumulate in aggregates. For Fir1 it was demonstrated that SUMOylation is essential for nuclear localization whereas SUMO-chain formation is not required for the nuclear localization but greatly enhances the formation of Fir1 aggregates. Additionally, it was observed that the SIM of Fir1 is required for aggregate formation. Colocalization experiments revealed that SUMO is part of the Fir1 aggregates itself. A whole cell proteome approach comparing wild-type cells with Uls2-deficient cells (slx5Δ) under non-stress and oxidative stress conditions revealed further promising candidates that might undergo Uls2-mediated quality control. In conclusion, the results of this thesis point toward a quality control mechanism involving the STUbL Uls2 for proteins with hidden SIMs or SUMOylation sites. This deepens our understanding of quality control of cytosolic proteins involving their relocalization to the nucleus. Further research should focus on elucidating the mechanism of nuclear import of the Uls2 targets as well as on investigating the proteins found in the proteomic approach.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Profe-Austermann, Friederike friederike.profe@gmx.com https://orcid.org/0009-0005-4202-5921 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-806116
Date:	8 July 2026
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language SUMO English Quality Control English SUMO-targeted Ubiquitin Ligases English Nis1 UNSPECIFIED Fir1 UNSPECIFIED
Date of oral exam:	20 March 2026
Referee:	Name Academic Title Dohmen, Jürgen Prof. Dr. Hofmann, Kay Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80611