Welcome to the Joazeiro lab!
E3 ubiquitin ligases: roles in signaling, protein quality control, and disease
Broadly, we are interested in the E3 ubiquitin ligases –their biological functions, mechanism of action, and roles in disease. For the past few years, we have focused on the problem of how cells know when its proteins are aberrant or damaged, and then decide on ways to either correct or eliminate them. Protein quality control is critical to ensure proteome integrity and cellular fitness; further underscoring its relevance, defective protein quality control is a hallmark of neurodegenerative diseases.
In eukaryotic organisms, key factors conferring specificity to protein quality control are molecular chaperones and E3 ligases. We have recently discovered a novel protein quality control mechanism mediated by an E3 ligase, Listerin/Ltn1, and which takes place on ribosomes. We now know that Listerin functions as a subunit of the Ribosome-Associated Quality Control (RQC) complex, which is conserved from yeast to humans. Of relevance, Listerin mutation causes motor neuron degeneration in mice.
We employ diverse model systems and approaches to elucidate how RQC-mediated quality control occurs at the cellular and molecular levels, including biochemistry, yeast genetics, cell biology, mouse models of neurodegeneration, and structural biology. We also analyze patients’ genomes to identify mutations that affect protein quality control; these studies are leading to insights onto the molecular basis of Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases, and to potential therapeutic targets.
In addition to the projects on Listerin, we have been working to elucidate the functions and mechanisms of the mitochondria-anchored E3 ligase, MULAN/MUL1, and to develop small molecule inhibitors of E3 ligases that can be used as oncology therapeutics.
Lyumkis, D., dos Passos, D.O., Tahara, E., Bennett, E., Vinterbo, S., Potter, C.S., Carragher, B. and Joazeiro, C.A.P. 2014. Structural Basis for Translational Surveillance by the Large Ribosomal Subunit-Associated Protein Quality Control Complex. Proc. Natl. Acad. Sci. USA 111:15981-6
Ossareh-Nazari, B., Niño, C.A., Bengtson, M.H., Lee, J.-W., Joazeiro, C.A.P. and Dargemont, C. 2014. Ubiquitylation by the Ltn1 E3 ligase protects 60S ribosomes from starvation-induced selective autophagy. J. Cell Biol. 204:909-919
Bengtson, M.H. and Joazeiro, C.A.P. 2010. Role of a ribosome-associated E3 ubiquitin ligase in protein quality control. Nature 467:470-473
Chu, J., Hong, N., Masuda, C., Jenkins, B., Nelms, K., Goodnow, C., Glynne, R., Wu, H., Masliah, E., Joazeiro, C.A.P. and Kay, S.A. 2009. A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration. Proc. Natl. Acad. Sci. USA 106: 2097-2103
Deshaies, R.J. and Joazeiro, C.A.P. 2009. RING Domain E3 Ubiquitin Ligases. Ann. Rev. Biochem. vol. 78: 399-434
Li, W., Bengtson, M., Ulbrich, A., Matsuda, A., Orth, A., Chanda, S., Batalov, S. and Joazeiro, C.A.P. 2008. Genome-wide and Functional Annotation of Human E3 Ubiquitin Ligases Identifies MULAN, a Mitochondrial E3 that Regulates the Organelle’s Dynamics and Signaling. PLoS ONE 3:e1487