Research Project 5:
Ubiquitin signaling regulating lysosome functions
Ubiquitination is one of the most powerful and complex posttranslational modifications (PTMs) of proteins. In addition to its function as a proteasomal degradation signal, ubiquitination also plays an important role in numerous non-proteolytic processes, it is a central regulator of selective autophagy and essential for cellular homeostasis.
Our project aims to characterize a novel role for this versatile PTM. Based on our preliminary results and recent data published by other research groups1-7, we suggest that ubiquitin signaling networks anchored at the surface of the lysosome control critical aspects of the organelle’s function, e.g. by contributing to the regulation of lysosome biogenesis, the transport of lysosomal enzymes, and the activation of membrane proteins in preparation of fusion events. In addition, we hypothesize that disruption of these ubiquitin regulatory networks at the lysosome contribute or are possibly even the cause of pathogenic effects observed in lysosomal storage diseases.
Taken together, our studies will allow for a better understanding of how ubiquitination affects the fate and function of individual lysosomal proteins and therefore controls lysosome biogenesis and lysosomal trafficking and fusion events. Further, we expect to gain new insight into the signaling events underlying pathophysiological changes in lysosomal storage diseases.
- Song P et al. (2016) Parkin Modulates Endosomal Organization and Function of the Endo-Lysosomal Pathway. J Neurosci 36:2425-37
- Gschweitl et al. (2016) A SPOPL/Cullin-3 ubiquitin ligase complex regulates endocytic trafficking by targeting EPS15 at endosomes. Elife 5:e13841
- Khaminets A et al. (2015) Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 522:354-8
- Xu C et al. (2014) Regulation of autophagy by E3 ubiquitin ligase RNF216 through BECN1 ubiquitination. Autophagy 10:2239-50
- Li M et al. (2015) Ubiquitin-dependent lysosomal membrane protein sorting and degradation. Mol Cell 57:467-78
- Li M et al. (2015) Membrane-anchored ubiquitin ligase complex is required for the turnover of lysosomal membrane proteins. J Cell Biol 211:639-52
- Papadopoulos C et al. (2017) VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J 36:135-150