Molecular insights into the targeting of proteins to the inner nuclear membrane

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Our cells are made up of several constituents, including proteins that we assemble inside a cellular compartment called cytoplasm. From there, these new proteins are targeted to various locations within the cell to perform their tasks. One of those locations is the nucleus, which contains our genetic information and is delimited by a double layered envelope. For soluble proteins, a variety of signals have been identified and nuclear import is mediated by small pores traversing the nuclear envelopes and a complex machinery involving, among others, proteins called importins and Ran. In contrast, membrane proteins destined for the nucleus reach that compartment by a poorly understood route implicating a loosely defined targeting signal. Characterizing this machinery is important since improper nuclear targeting of these proteins would hamper their functions. Viruses are intracellular parasites that depend on cellular machineries for their propagation. This makes them ideal tools to study how we function, since much simpler than us. Among them, Herpes simplex virus type I (nicknamed HSV-1) is commonly associated with cold sores but can also cause several more severe conditions. It codes for several proteins that are targeted to nuclear membranes. As for cellular proteins, it is however not clear how they reach that compartment but are presumed to use the cellular sorting machinery. Interestingly, these proteins are dynamically re-localized throughout the infection, raising the intriguing possibility that the virus can finely regulate this transport apparatus. This makes it an exciting model to better understand protein targeting to the nuclear membranes. Among them, the HSV-1 glycoprotein M (gM) possesses a potential nuclear membrane sorting motif and is the first of several viral proteins detected on nuclear membranes. Later on, it moves to other cellular compartments as the infection proceeds and current evidence points to the implication of cellular and/or additional viral components modulating its localization. The viral gM protein thus constitutes an excellent candidate to study the nuclear targeting machinery and define how it is regulated. The long term goals of our research program are to understand the targeting of proteins to the nuclear membranes, clarify the role of these proteins there, probe the universality of this sorting machinery and define how viruses modulate it. Our specific Aims for the next 5 years are to 1) Elucidate the molecular basis of INM targeting, using HSV-1 gM as a model protein; 2) Examine the role of cellular importins for gM nuclear localization and 3) Characterize the mammalian E-Syt1, a novel gM interaction partner we recently identified. This work is highly innovative both because it relies on state-of-the-art technologies and investigates novel host-pathogen interactions with potentially far ranging implications in cell biology and virology.