Intracellular protein degradation via the ubiquitin-proteasome system (UPS) is an essential process that maintains protein homeostasis. However, selective destruction of regulatory proteins also provides an important control mechanism for quickly and irreversibly eliminating signaling proteins such as cyclins and transcription factors, and is therefore relevant for most cellular and physiological functions including cell cycle progression, differentiation and DNA repair. However, in addition the UPS is also an active participant of the so-called protein quality control (PQC) network that has evolved to monitor the folding of cellular proteins and ensure that potentially toxic structurally destabilized or misfolded proteins are eliminated from the cell. In the present PhD thesis, two projects were undertaken. In one the structure and function of the phylogenetically conserved proteasome subunit Dss1 was analyzed by a combination of NMR spectroscopy and proteomics using the fission yeast Schizosaccharomyces pombe as a model organism. The presented data show that Dss1 is an intrinsically disordered protein capable of interacting with a broad range of different protein complexes, including the 26S proteasome, the TREX2 mRNA export complex, the single stranded DNA binding complex RPA and others. It is shown that Dss1 forms a transiently populated C-terminal helix that dynamically interacts with and shields a central binding region. This helix interfered with the interaction to ATP-citrate lyase but was required for septin binding, and in strains lacking Dss1, ATP-citrate lyase solubility was reduced, and septin rings were more persistent. In the other project, the proteasomal degradation of disease-linked missense variants of the HPRT protein was explored in human cells and in the budding yeast Saccharomyces cerevisiae. By in silico saturation mutagenesis and biophysical calculations using the crystal structure of HPRT it is shown that many disease-linked HPRT missense variants are predicted to cause a destabilization of the HPRT protein. Accordingly, several disease-linked HPRT variants are present at reduced steady-state levels due to rapid degradation via the UPS. High-throughput stability and functional analyses using genetic systems in yeast revealed that many disease-linked HPRT protein variants are present at reduced levels in cells and are non-functional. Correlation of HPRT abundance and function with the in silico stability predictions allow the provided computational protein stability predictions to identify pathogenic missense variants that operate by destabilizing the HPRT protein.