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Jungsan Sohn

Johns Hopkins University, USA

Title: Assembly mechanism of foreign dsDNA-sensing inflammasomes

Biography

Biography: Jungsan Sohn

Abstract

Absent-in-melanoma-2-like receptors (ALRs) detect foreign double-stranded (ds)DNA from invading pathogens and assemble into filamentous signaling platforms termed inflammasome. The ALR filaments play crucial roles in launching antiviral and inflammatory responses against a number of pathogens (e.g. HIV and HSV); however, persistent ALR complexes are also linked to autoimmune disorders (e.g. Sjögren’s syndrome and lupus). Here, by combining solution assays, electron microscopy, and single-molecule methods, we investigate the filament assembly mechanisms of two prototypical ALRs, namely IFI16 and AIM2.

(1) IFI16 detects foreign dsDNA both in the host nucleus and cytoplasm. We found that IFI16 uses dsDNA as a one-dimensional diffusion-scaffold to assemble into filaments. The dsDNA-binding HIN200 domains of IFI16 are responsible for tracking dsDNA, while its pyrin domain (PYD) is necessary for filament assembly. Importantly, nucleosomes represent barriers that prevent IFI16 from targeting host dsDNA by directly interfering with its assembly. This unique scanning-assisted assembly mechanism would allow IFI16 to distinguish self- from nonself-dsDNA in the nucleus.

(2) AIM2 detects cytoplasmic dsDNA and assembles into an inflammasome. We found that the PYD of AIM2 (AIM2PYD) drives both filament formation and dsDNA binding. As with IFI16, the size of exposed dsDNA acts a key regulator for the polymerization of AIM2. The helical symmetry of the upstream AIM2PYD filament is consistent with the filament assembled by the PYD of the downstream ASC adaptor, indicating that AIM2 acts as a structural template for polymerizing ASC.

Together, our studies provide a unifying paradigm for how ALRs carry out foreign dsDNA-sensing pathways, where generating a structural template by coupling ligand-binding and oligomerization plays a key signal transduction mechanism.

References:

  1. Morrone, S.M., Wang, T., Constantoulakis, L.M., Hooy, R.M., Delannoy, M.R., and Sohn, J. (2014) Cooperative assembly of IFI16 filaments on dsDNA provides insights into host defense strategy.  PNAS 111, E62-71
  2. Geertsma, H.J., Schute, A.C., Spenkelink, L.M., Mcgrath, W.J., Morrone, S.R., Sohn, J., Mangel, W.F., Robinson, A., van Oijen, (2015) A. Single-molecule imaging at high fluorophore concentrations of Dye (LaDYe). Biophysical Journal 108, 949-56.
  3. Baer, A.N., Petri, M.A., Sohn, J., Rosen, A., Casciola-Rosen, L. Antibodies to human IFI16 are present in systemic lupus and primary Sjögren’s syndrome with similar frequencies but detect different parts of molecule. (2015) Arthritis Care Res.
  4. Morrone, S.M. Matyszewski, M., Yu, X., Delannoy, M., Egelman, E.H., and Sohn J. Assembly driven activation of the AIM2 inflammasome provides a template for the polymerization of downstream ASC. (2015) Nature Communications. 6, 7827.
  5. Stratmann, S., Morrone, S.M., van Oijen, A.M.*, and Sohn, J*. The innate immune sensor IFI16 recognizes foreign DNA in the nucleus by scanning along the duplex. (2015). eLife e11721  *: co-corresponding authors