An expanding universe of membrane remodelling events, the role of ESCRTs in cell biology and human disease
Speaker: Professor Juan Martin-Serrano, Division of Immunology, Infection and Inflammatory Disease
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Abstract: The last step in the assembly of enveloped viruses requires the physical separation of the budding virion from the infected cell. Consequently, the vast majority of these viruses encode late assembly domains (L-domains) that facilitate the membrane remodelling events required for virion egress. The high degree of conservation between L-domains encoded by very divergent pathogens such as HIV-1 and Ebola virus suggested that their role in viral budding could involve the recruitment of cellular proteins.
This lecture will summarise the work that led to the identification of the Endosomal Sorting Complexes Required for Transport (ESCRT) pathway as the cellular machinery recruited by L-domains to facilitate viral budding. I will also cover how these findings led to the identification of the mechanism underlying cytokinetic abscission, the final event in cell division that promotes the physical separation of the daughter cells.
I will then discuss our recent work identifying CHMP4C and ULK3 as key human proteins that regulate abscission to prevent the damage of unsegregated chromosomes by the cytokinetic machinery. Specifically, I will discuss the cascade of signalling events involving CHMP4C and ULK3 in abscission regulation, and how these regulatory events are likely to be involved in ovarian cancer. Lastly I will discuss our current work aimed to better understand the regulatory events that coordinate the membrane remodelling activity of the ESCRT machinery to ensure the sealing of the nuclear envelope during mitosis.
About the speaker: Professor Juan Martin-Serrano received his PhD from Universidad Autonoma de Madrid in 1999. He then moved to New York to join the laboratory of Paul Bieniasz at the Aaron Diamond AIDS Research Centre, Rockefeller University. During this period he made some of the pioneering observations that uncovered the mechanisms employed by enveloped viruses to promote particle assembly and release. Specifically, he showed that ESCRT-associated host factors including Tsg101 and HECT ubiquitin ligases are recruited by divergent enveloped viruses such as Human Immunodeficiency Virus-1 and Ebola Virus to promote their egress. This work also revealed the modular nature of the ESCRT machinery as a principle that paved the way to uncover novel functions of this pathway in cell biology.
Professor Martin-Serrano was recruited to the Infectious Diseases Department at KCL in 2004, where he became interested in the intersection between virology and cell biology, exploiting how these disciplines illuminate each other. His laboratory has identified novel cellular factors that provide functional specificity within the ESCRT pathway, such as ESCRT-associated proteins that are involved in ubiquitin binding (UBAP1) and hydrolysis (AMSH) in the context of endosomal sorting. Work from his group has also established the unforeseen role of the ESCRT machinery in the final separation of the daughter cells, thus contributing to our understanding of the basic principles underlying cell division. Further work in this area has uncovered mechanisms that coordinate the final events in human cell division with chromosome segregation. These monitoring mechanisms avoid catastrophic consequences for genome stability associated with aberrant cell division, suggesting potential links with human cancer. During this time at KCL Professor Martin-Serrano has been selected for the EMBO Young Investigator Programme, and he has been awarded the Lister Prize and the GlaxoSmithKline Award by the Biochemical Society.