RT Journal Article SR Electronic T1 Cell-autonomous Toxoplasma killing program requires Irgm2 but not its microbe vacuolar localization JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202000960 DO 10.26508/lsa.202000960 VO 4 IS 7 A1 Ariel Pradipta A1 Miwa Sasai A1 Kou Motani A1 Ji Su Ma A1 Youngae Lee A1 Hidetaka Kosako A1 Masahiro Yamamoto YR 2021 UL https://www.life-science-alliance.org/content/4/7/e202000960.abstract AB Interferon-inducible GTPases, such as immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs), are essential for cell-autonomous immunity against a wide variety of intracellular pathogens including Toxoplasma. IRGs comprise regulatory and effector subfamily proteins. Regulatory IRGs Irgm1 and Irgm3 play important roles in anti-Toxoplasma immunity by globally controlling effector IRGs and GBPs. There is a remaining regulatory IRG, called Irgm2, which highly accumulates on parasitophorous vacuole membranes (PVMs). Very little is known about the mechanism of the unique localization on Toxoplasma PVMs. Here, we show that Irgm2 is important to control parasite killing through recruitment of Gbp1 and Irgb6, which does not require Irgm2 localization at Toxoplasma PVMs. Ubiquitination of Irgm2 in the cytosol, but not at the PVM, is also important for parasite killing through recruitment of Gbp1 to the PVM. Conversely, PVM ubiquitination and p62/Sqstm1 loading at later time points post-Toxoplasma infection require Irgm2 localization at the PVM. Irgm2-deficient mice are highly susceptible to Toxoplasma infection. Taken together, these data indicate that Irgm2 selectively controls accumulation of anti-Toxoplasma effectors to the vacuole in a manner dependent or independent on Irgm2 localization at the Toxoplasma PVM, which mediates parasite killing.