Molecular basis of IRGB10 oligomerization and membrane association for pathogen membrane disruption

Abstract

Immunity-related GTPase B10 (IRGB10) belongs to the interferon (IFN)-inducible GTPases, a family of proteins critical to host defense. It is induced by IFNs after pathogen infection, and plays a role in liberating pathogenic ligands for the activation of the inflammasome by directly disrupting the pathogen membrane. Although IRGB10 has been intensively studied owing to its functional importance in the cell-autonomous immune response, the molecular mechanism of IRGB10-mediated microbial membrane disruption is still unclear. In this study, we report the structure of mouse IRGB10. Our structural study showed that IRGB10 bound to GDP forms an inactive head-to-head dimer. Further structural analysis and comparisons indicated that IRGB10 might change its conformation to activate its membrane-binding and disruptive functions. Based on this observation, we propose a model of the working mechanism of IRGB10 during pathogen membrane disruption.

Structural basis of membrane recognition of Toxoplasma gondii vacuole by Irgb6

“…The overall architectures of Irgb6 are similar with previously solved Irga6 or Irgb10 structures (Ghosh et al, 2004; Ha et al, 2021). They consist of an N-terminal helical domain (N-domain; amino acids 1-55; αA– αC) (blue in Fig.…”

“…1 D). It should be noted that, in the Irga6 or Irgb10 structure, these helices αd and H4 serve as an interface for homo-dimerization (Pawlowski et al, 2011; Schulte et al, 2016; Ha et al, 2021). Homo-dimerization is thought to be required to activate the GTPase of IRGs.…”

“…Irga6 structures were reported in three states with GMPPNP (PDB ID: 1TQ2), GDP (PDB ID:1TPZ), and without any nucleotide (PDB ID: 1TQD) (Ghosh et al, 2004). The Irgb10 structure was reported in the GDP state (PDB ID: 7C3K) (Ha et al, 2021). We thus compared our Irgb6 structures with these four structures.…”

“…In our GTP-bound structure, therefore, Irgb6 only recognizes a “GDP part” of GTP so that it resembles the GDP form of IRG proteins. By analogy with Irga6 or Irgb10 (Ghosh et al, 2004; Ha et al, 2021), homo-dimerization of Irbg6 might trigger the isomerization of the G-domain to assume the active GTP form.…”

“…Recent reports of crystal structures of Irga6 in various nucleotide states and Irgb10 in the GDP state elucidated the basic architecture of IRGs, consisting of a GTPase domain and N-terminal and C-terminal helical domains (Ghosh et al, 2004; Ha et al, 2021). Structural studies also indicated that homo-dimerization through the GTPase domain interface is required to activate the GTPase of IRG proteins (Pawlowski et al, 2011; Schulte et al, 2016; Ha et al, 2021). However, the structural mechanism of PVM recognition is still vague.…”