| dc.description.abstracteng | From early neurogenesis to the maintenance of post-mitotic neurons, apoptosis plays a pivotal role. Uncontrolled apoptotic events can lead to abnormal neuronal cell loss, which is a hallmark of various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease or Huntington's disease. As an important protein quality control, the ubiquitin-mediated proteasomal degradation is crucially involved in the apoptotic events. E3 ligases are the most abundant proteins in the ubiquitin-proteasome system that confer the target specificity and catalyze ubiquitination of substrates. Among those, the RING (Really Interesting New Gene)-type E3 ligases consisting of more than 600 members represent the most numerous components in ubiquitination.
In this study, I show that the brain-dominant protein RNF157, a RING-type E3 ligase, is present exclusively in the cytoplasm. In addition, together with our previous finding, my functional analyses revealed that RNF157 promotes neuronal survival in hippocampal neurons. Further epistasis analyses demonstrated that the newly identified interator of RNF157, the adaptor protein Fe65, operates downstream of RNF157 in regulating neuronal survival. Notably, RNF157 ubiquinates Fe65 via a K63-linked ubiquitin chain and targets Fe65 non-canonically for protesasomal degradation, thus inhibiting the pro-apoptotic function of Fe65.
In addition, I found that nuclear Fe65 is the main contributor in triggering apoptosis in hippocampal neurons as compared to cytoplasmic Fe65. Subsequently, I explored if any nuclear interactors of Fe65 are involved in the RNF157/Fe65 pathway. While the histone acetyltransferase Tip60 does not induce cell death, the novel interactor of Fe65, the RNA-binding protein Tip110, induces neuronal apoptosis. Epistasis analysis indicates that Tip110 acts downstream in the RNF157/Fe65 pathway to regulate neuronal survival.
Furthermore, I investigated if RNF157 has a role in mouse behavior. Using the RNF157 knockout mouse model, I found that loss of RNF157 has no impact on the hippocampus-mediated working and spatial memory. Instead, mice lacking RNF157 exhibit impairments in amygdala-mediated fear memory. To sum up, my study discloses a novel RNF157/Fe65/Tip110 pathway in the control of neuronal survival at the cellular level and the importance of RNF157 in cognitive functions. This provides a further insight into the role of E3 ligases in regulating neuronal apoptosis, and thus into mechanisms leading to neurodegeneration. | de |