TRIM proteins in autophagy-mediated antiviral defense

• Applicant: Dr. Konstantin Sparrer
• Subject Area: Immunology ; Virology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 276722842

The innate immune system is the first defense mechanism of a host against invading viral pathogens. It serves as a quick response by inducing antiviral cytokines, most prominently type-I interferons (IFNs), which subsequently lead to the gene expression of a large variety of antiviral proteins. In addition, the innate immune system stimulates the adaptive immune response to facilitate clearance of an infection. Recent evidence indicates that signaling pathways of the innate immune system are tightly interconnected with and regulated by autophagy. Autophagy has been increasingly appreciated as a critical cell-intrinsic mechanism in the antiviral innate immune defense. Defects in autophagy have been shown to positively influence the susceptibility to pathogen infections, and in fact, many viruses induce an autophagic response upon infecting a cell, including the important human pathogen influenza A virus (IAV). The goal of this project is to identify novel cellular factors mediating autophagy induction in response to IAV infection and to characterize these factors with respect to their physiological role in antiviral innate immunity. Tripartite motif (TRIM) proteins have emerged as an important class of molecules in IFN-mediated antiviral innate immunity. Furthermore, it has been recently reported that TRIM proteins play roles in regulating autophagy; however, the exact role and impact of autophagy induction by TRIM proteins on antiviral immune defenses are completely unknown. Intriguingly, as shown in the preliminary data, several TRIM proteins, and in particular TRIM25, play a role in specifically virus-induced autophagy. To systematically determine the role of TRIM proteins in virus-induced autophagy, the applicant will screen a shRNA library targeting all known human TRIM proteins for modulation of autophagy during infection with IAV. The identified autophagy-modulating TRIM proteins will be further characterized regarding their functional domains, their modes of autophagy activation, and their interaction partners. Subsequently, their physiological role in the cell-intrinsic antiviral defense against IAV and other viruses will be analyzed. New insights into the interplay between TRIM-mediated autophagy and their roles in the IFN response, as well as into their autophagy-dependent antiviral activities, will help to delineate in mechanistic depth the role of autophagy as an innate antiviral defense mechanism.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Michaela Gack