C. elegans provides an excellent model system with which to investigate the ubiquitin pathway. The process of ubiquitination of target proteins is accomplished by a three step pathway (see figure above). Ubiquitination affects proteins by leading to their degradation or causing a change in their cellular localization or activity. An interesting hierarchy exists in the pathway. Most organisms contain a single E1 activating enzyme, several E2 conjugating enzymes (Ubc), and over 100 E3 ubiquitin ligases.

We are using RNAi, as well as biochemical and yeast two-hybrid assays to determine relationships between specific ubiquitin ligases and ubiquitin conjugating enzymes. Our studies have revealed a link between the RING finger ligase, APC, and ubc-2 (Frazier et al, 2004). The ubc-2 RNAi phenotype and two-hybrid data indicate that ubc-2 might also function with other ligases. Future studies will attempt to identify those match-ups.

In addition, we have tested the how the Ubc's are involved in protein aggregation using a worm model for polyglutamine aggregation (Satyal et al., 2000). Polyglutamine aggregates form in the neurons of patients with certain neurodegenerative diseases such as Huntington's Disease. Our results show that certain Ubc's are required for polyglutamine aggregates to achieve their normal size and number (Howard et al, 2007). We are continuing to investigate how the ubiquitin pathway affects the development of polyglutamine aggregates and whether the ubiquitin pathway could be a therapeutic target for diseases of protein misfolding.

The predicted C. elegans ubiquitin conjugating enzymes and RING finger ligases are shown below.

RNAi phenotypes of
Ubiquitin Conjugating Enzymes
in C. elegans