Negative regulation of the antiviral response by TRIM52

The immune system is critical to protect us from infections by the numerous pathogens we encounter on a daily basis. It is important that the anti-microbial response is only activated during infection to prevent hyper-inflammation and auto-immunity. To avoid accidental activation, factors are in place, which generate an activation threshold: so-called base-line inhibitors. However, these base line inhibitors work on a molecular level to achieve this activation threshold remains poorly understood. We recently identified a member of the tripartite motif protein family as a likely base-line inhibitor, which limits the predominant antiviral response system. In the context of this grant we will determine how this factor limits the immune response at the molecular level, which will aid in determining its relevance for preventing auto-immune disease. Together, the proposed work will expand our understanding of how the antiviral response is inhibited during resting conditions, and during physiological resolution of infection, how deregulation of these responses contribute to auto-immune diseases, and ultimately how to better diagnose immune disorders and design intervention strategies.

Cells need to be able to adapt to constant changes in their environment, yet maintain a safe intra-cellular environment. This is in particular important for our genetic material -DNA-, as mutations therein can result in cancer. Given the importance to protect our DNA, factors that do so are present from low complexity species all the way up to humans. In line with this notion, such factors are routinely evolutionary conserved. We discovered that a rather unknown factor called TRIM52 forms an interesting exception: it is not conserved in mammals, yet plays a crucial role in maintaining genome integrity in humans. Its importance is underpinned by the fact that experimental removal of TRIM52 from cells, increases DNA damage and makes it that cells stop growing as a defense mechanism. Investigating how cells make sure that we always have appropriate amounts of TRIM52, we discovered that when cells make TRIM52, they almost immediately degrade it. An important question that came from this observation, and that we will further pursue in future projects, is why a cell would make such a factor that is immediately degraded. Our current work identified three novel cellular factors that mediate this extraordinarily rapid degradation. These novel factors are very large for cellular standards, and their targets and mode of action have been enigmatic. Our work showed that these three degraders work independently of each other to mark TRIM52 for destruction, in part explaining how TRIM52 is so rapidly turned over. Moreover, we discovered that all three degraders recognize and target different parts of TRIM52. One of the three major recognition sites in TRIM52 was identified as an unstructured region with strong negative charge, suggesting that other human proteins with such a feature may be targeted in a similar manner. Together, our data from this project have provided mechanistic insight into how enigmatic degraders can recognize their targets, and mark them for destruction. These results have laid the foundation for future work to unravel why cells employ such degradation mechanisms to keep TRIM52 levels low, and how this is relevant for TRIM52 function in ensuring DNA integrity. An enticing possibility is that the cellular pool of TRIM52 is kept low in the absence of DNA damage by constant degradation, whereas this rapid destruction is blocked at times of mutagenic stress, which would allow cells to rapidly respond to genotoxic stress. Moreover, this work has enabled future work to investigate why humans and primates specifically have maintained this factor in evolution, whereas many other mammals have not.