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

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Our cells contain thousands of different proteins, which are assembled inside a subcompartment called cytoplasm. From there, they are targeted to a variety of cellular locations to perform their tasks. One of these destinations is the nucleus, which contains our genetic information and is delimited by a double-layered envelope. For proteins reaching the nuclear matrix, several signals have been identified and nuclear import is mediated by a complex machinery operating through small holes traversing the nuclear envelopes. In contrast, the molecular details by which proteins are inserted within the innermost nuclear envelope are still nebulous and clarifying them is critical to better understand the function of these proteins. 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, the Herpes simplex virus type I (HSV-1) is the virus commonly associated with cold sores but it also causes a plethora of more severe diseases such as encephalitis and blindness. Some of HSV-1 viral proteins are targeted to nuclear membranes. As for cellular proteins, it is, however, not clear how they reach that compartment but they likely rely on an existing cellular apparatus. Interestingly, these viral proteins are dynamically re-localized during the infection, raising the intriguing possibility that the virus can spatially and temporally regulate this cellular transport machinery. This makes HSV-1 an exciting model to better understand targeting of proteins to the nuclear envelopes. Among them, the viral glycoprotein M (gM) possesses a potential nuclear membrane sorting motif and is the first of several viral proteins detected there. This viral glycoprotein moves out of the nucleus as the infection proceeds, indicating that its localization is influenced by cellular and/or other viral components. Our recent experiments hint at several novel gM interaction partners. The viral gM protein thus constitutes a great candidate to study this cellular targeting process and define how viruses modulate it. The long-term goals of our research program are to understand the targeting of proteins to the nuclear membranes, probe the universality of this sorting machinery and define if and how viruses regulate it. Our specific aims for the next 5 years are to A) Probe how gM is brought to the inner nuclear targeting, B) Clarify the role of nuclear channels between the nucleus and the rest of the cell and C) Figure out how gM is ultimately released from the nucleus. To reach these goals, a vast array of modern and complementary technologies will be employed, including imaging techniques as well as virology, cell biology and system biology tools.