Dynamic Organelle Remodeling: Viral Mechanisms to Subvert Host Cell Biology
Ileana Cristea is a Professor in the Department of Molecular Biology at Princeton University. Her laboratory focuses on characterizing mechanisms of cellular defense against viruses, as well as mechanisms used by viruses to manipulate these critical cellular processes. Towards these goals, she has promoted the integration of virology with proteomics and bioinformatics. She has developed methods for studying virus-host protein interactions in space and time during the progression of an infection, which have allowed her group to bridge developments in mass spectrometry to important findings in virology. For example, her laboratory has contributed to the emergence of the research field of nuclear DNA sensing in immune response, and has discovered sirtuins as broad-spectrum antiviral factors.
(This will be a hybrid lecture, in person at Lipsett Amphitheather and on NIH VideoCast.) Organelle remodeling is an essential component of all human virus infections. Viruses rely on the biological processes partitioned within organelles for their infectious cycles. Likewise, host cells require organelles to detect and combat pathogen invasion. Here, we integrate molecular virology, super-resolution microscopy, and proteomics to characterize organelle structure-function relationships in the context of viral infections. Among the highlighted studies is our recent characterization of membrane contact site proteins (MCSs), which link organelles to coordinate cellular functions across space and time. We define functional virus-driven MCS alterations by ancient and emerging human viruses: human cytomegalovirus (HCMV), herpes simplex virus (HSV-1), influenza A (Infl. A), and the beta-coronavirus HCoV-OC43. We find that viral regulation of organelle contacts is time-sensitive and organelle-specific, providing a molecular basis for switching anti- to pro-viral organelle structures and functions. We uncover a stabilized mitochondria-ER encapsulation structure that we term MENC, and which supports virus production during HCMV infection. At peroxisomes, ACBD5-mediated ER contacts balance peroxisome proliferation versus membrane expansion, with ACBD5 impacting the titers of each virus tested. By characterizing the global virus-directed modulation of MCSs, we uncover molecular fingerprints of organelle remodeling linked to infection progression and pathogenesis.
- To understand the relevance of organelle remodeling during infection with human viruses
- To gain an appreciation for the ability of integrative proteomics and microscopy approaches to provide insights into organelle structure-function relationships
- To consider structural remodeling events involved in regulating mitochondrial bioenergetics and cellular metabolism during viral infections
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