The role of autophagy during viral infection
Final Report Abstract
Tripartite Motif (TRIM) and ADP-ribosylation factor (ARF) proteins play important regulatory roles in our innate immune system's response to viruses. TRIM proteins are very well-known to positively regulate innate immune processes. However, it was little understood whether TRIM proteins can also reduce innate immune activation, thus being interesting targets for therapy that relies on inducing innate defenses. Here we have identified three TRIM proteins (TRIM2, TRIM3, and TRIM71) that inhibit autophagy, a part of the innate immune system. These three proteins interact with a kinase called CK2 and are phosphorylated by it, which is necessary for their activity. Interestingly, inhibiting CK2 can promote autophagy and help fight viruses like influenza A and measles. Members of the family of ARF proteins are crucial for cellular trafficking processes i.e. transporting proteins from one part of a cell to another. Here we focused on a specific member of the called ARF1 that we had identified to be important for our immune system's response to viruses. We discovered that a mutation or defect in ARF1 is the cause of a rare disease called a type I interferonopathy, which causes chronic inflammation i.e. too much innate immune activation. Surprisingly, the mutation affects the function of ARF1 in maintaining the integrity of mitochondria (the cell's energy generators) and in the recycling of a molecule called STING, which helps to detect viruses. The malfunctioning of ARF1 leads to the release of mitochondrial DNA, which activates a signalling pathway that eventually causes inflammation. Our discoveries provide important new insights into how our immune system functions and how we might be able to better fight viral infections. We propose modulation of CK2 as means to activate antiviral autophagy, and helped to explain the underlying reasons for an anti-inflammatory disease.
Publications
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Luciferase reporter assays to monitor interferon signaling modulation by SARS-CoV-2 proteins. STAR Protocols, 2(4), 100781.
Hirschenberger, Maximilian; Hayn, Manuel; Laliberté, Alexandre; Koepke, Lennart; Kirchhoff, Frank & Sparrer, Konstantin Maria Johannes
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Manipulation of autophagy by SARS-CoV-2 proteins. Autophagy, 17(9), 2659-2661.
Koepke, Lennart; Hirschenberger, Maximilian; Hayn, Manuel; Kirchhoff, Frank & Sparrer, Konstantin MJ
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Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities. Cell Reports, 35(7), 109126.
Hayn, Manuel; Hirschenberger, Maximilian; Koepke, Lennart; Nchioua, Rayhane; Straub, Jan Hendrik; Klute, Susanne; Hunszinger, Victoria; Zech, Fabian; Prelli, Bozzo Caterina; Aftab, Wasim; Christensen, Maria Hønholt; Conzelmann, Carina; Müller, Janis Alexander; Srinivasachar, Badarinarayan Smitha; Stürzel, Christina Martina; Forne, Ignasi; Stenger, Steffen; Conzelmann, Karl-Klaus; Münch, Jan ... & Sparrer, Konstantin Maria Johannes
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The antiviral activities of TRIM proteins. Current Opinion in Microbiology, 59, 50-57.
Koepke, Lennart; Gack, Michaela U. & Sparrer, Konstantin MJ
