Inactive and active states of the interferon-inducible resistance GTPase, Irga6, In Vivo

J Biol Chem. 2008 Sep 10. [Epub ahead of print]

Inactive and active states of the interferon-inducible resistance GTPase, Irga6, In Vivo

Papic N, Hunn JP, Pawlowski N, Zerrahn J, Howard JC.

Department of Cell Genetics, Institute for Genetics, University of Cologne, Cologne 50674.

Irga6, a myristoylated, interferon-inducible member of the Immunity-Related GTPase (IRG) family, contributes to disease resistance against Toxoplasma gondii in mice. Accumulation of Irga6 on the T. gondii parasitophorous vacuole membrane (PVM) is associated with vesiculation and ultimately disruption of the vacuolar membrane in a process that requires an intact GTP-binding domain. The role of the GTP binding domain of Irga6 in pathogen resistance is, however, unclear. We provide evidence that Irga6 in interferon-induced, uninfected cells is predominantly in a GDP-bound state that is maintained by other interferon-induced proteins. However Irga6 that accumulates on the PVM after Toxoplasma infection is in the GTP-bound form. We demonstrate that a monoclonal antibody, 10D7, specifically detects GTP-bound Irga6, and we show that the formation of the 10D7 epitope follows from a GTP-dependent conformational transition of the N-terminus of Irga6, anticipating an important role of the myristoyl group on Irga6 function in vivo.

PMID: 18784077 [PubMed - as supplied by publisher]