Cell growth and division are tightly regulated by phosphorylation and selective degradation of cellular components. Whereas autophagy is mainly responsible to eliminate long-lived proteins and organelles, the ubiquitin-proteasome system (UPS) rapidly degrades proteins when fast adaptation is needed. Defects in these degradation systems accounts for numerous human diseases, including cancer, muscle dystrophies, viral and bacterial infections and neurodegeneration. While rapid progress has been made in the identification of UPS and autophagy components, little is known about their regulation and the molecular mechanisms that ensure substrate specificity. We therefore propose an interdisciplinary combination of biochemistry, cell and structural biology, genetics, RNAi-screening, quantitative microscopy and microfluidic technology to tackle these questions in yeast and mammalian cells.E3 ubiquitin ligase complexes are important UPS components that specifically bind substrates via dedicated adaptors. In particular, cullin-based E3-ligases control cell growth and division, but much needs to be learned about their regulation and the identity and function of their key substrates. Moreover, we uncovered a function of RING-H2 E3-ligases in MAP-kinase networks, providing a new link between phosphorylation and the UPS. Finally, while autophagy can selectively remove protein aggregates and damaged or excess organelles, the underlying mechanisms that provide specificity to this process are poorly understood. Recent evidence suggests that ubiquitin may also serve as a recognition signal for selective autophagy. We will thus investigate the roles of ubiquitin and specific autophagy substrate-adaptors, and focus on the molecular crosstalk between selective autophagy and the UPS.