Resolving functional aggregates: A new perspective on innate immune control

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Pattern Recognition Receptors (PRRs) in the innate immune system form the first line of defense against a broad range of pathogens. PRRs and their downstream signaling molecules often form aggregate-like macromolecular assemblies and that they utilize such assemblies for their immunological functions. These findings have transformed our understanding of how the innate immune system detects microbial infection and how it activates the anti-microbial immune response. However, how these “functional aggregates” are resolved upon their assembly to ensure transient activation of the potentially harmful inflammatory signal is not known. How do these functional aggregates interact with the cellular protein quality control (PQC) system, charged with resolving misfolded protein aggregates (e.g. amyloids)? Is there a commonality or rather a divergence in cellular response to functional vs. dysfunctional misfolded aggregates? The current application aims to address these questions by exploring the connections between innate immunity and PQC. This is uncharted territory, with only few relevant studies that address such questions. Our strategy is to utilize multidisciplinary approaches, from systematic functional screens to biochemical reconstitution and to structural dissection. The combination of these approaches is sure to generate deep mechanistic understanding of how functional aggregates in innate immunity are resolved. It will also provide a new paradigm for how the innate immune system is regulated and how it can be further controlled for therapeutic gains. Furthermore, considering the emerging view that many proteins form aggregates-like assemblies or granules as part of normal physiology (e.g. cytosolic RNA granules and nuclear speckles), our findings and strategies have implications far beyond the innate immune system. The current application represents a new direction in my research. Unlike our previous and current work, which has largely focused on the mechanisms of how microbial infection activates innate immune response, this application focuses on the mechanisms of how cells turn off the immune signaling once activated. In particular, I propose to explore the previously unappreciated interface between innate immunity and cellular PQC, seeking new unifying principles governing both innate immune signaling complexes and misfolded dysfunctional aggregates. Underlying this application is my general scientific approach of identifying novel connections between disciplines and pushing the existing boundaries of the fields. While this proposal deals with highly risky and challenging problems, as one of the pioneering laboratories for the discovery of functional aggregates in innate immunity, I believe that we are uniquely positioned to open this new area of research.