Discovery of the RING domain E3 ubiquitin ligase family

During post-doctoral work, while investigating how the duration and amplitude of kinase signaling is kept in check, we showed that the negative regulator of receptor tyrosine kinases, c-Cbl, acts as an E3 ligase (Joazeiro et al. 1999). We found that c-Cbl recognizes activated receptors through its variant SH2 domain and recruits E2 ubiquitin conjugating enzymes via its RING domain; c-Cbl then stimulates ubiquitin transfer from the E2 to receptors, to promote their degradation. Following this breakthrough discovery, we provided evidence, together with other labs, that RING domain proteins indeed have a general function as E3 ligases, greatly expanding the number of known and potential E3s (see Publication List).

The human genome encodes over 650 E3 ligases

It had long been anticipated that many E3 ligases must exist in order to account for specificity on the ubiquitylation of thousands of different proteins. To address this issue, our team set out to generate a comprehensive, genome-wide inventory of predicted human E3 ligases. The analyses identified and mapped over 650 E3-encoding genes, ~95% of which depend on a RING domain (Li et al. 2008; Deshaies & Joazeiro 2009). This inventory has enabled generating tools for functional genomic analyses focused on the E3 ligase family. As many E3 ligases play critical roles in biology and are directly implicated in disease (e.g., Parkin, Mdm2, BRCA1, to name a few), research into this family will continue to be a rich source of discoveries.

Mutation in the E3 ligase Ltn1/Listerin causes motor neurodegeneration in mice

We have reported that mice with a mutation in a previously unstudied gene, encoding the Listerin/LTN1 E3 ligase, develop neurologic and motor dysfunction similar to mouse models of Amyotrophic Lateral Sclerosis (ALS) (Chu et al 2009). ALS, a severely debilitating disease, took the lives of the American baseball player, Lou Gehrig, and the British physicist, Stephen Hawking. ALS gained further notoriety more recently, due to the ‘ice-bucket competition’ that highlighted the need for more research towards understanding and treating the disease. Genetic mouse models, like the Listerin-mutant mice, can provide insight into the pathogenesis and molecular pathways underlying ALS and other neurodegenerative diseases.

Discovery of Ribosome-associated Quality Control

The finding that Listerin mutation causes neurodegeneration in mice raised the questions of what Listerin’s normal function is, and how a defect in this function results in the phenotype. Our curiosity to know the answers to these questions led to the discovery that Listerin mediates Ribosome-associated Quality Control (RQC), a novel protein quality control pathway (Bengtson & Joazeiro 2010). Importantly, this finding provided the first link between RQC and neurodegeneration, which is consistent with the knowledge that defective protein quality control is a hallmark of human neurodegenerative diseases. See the RESEARCH tab to learn about how we have continued to shape the RQC field, as well as future directions we plan to take.