Neutrophil direction sensing and superoxide production linked by the GTPase-activating protein GIT2

Yuichi Mazaki¹, Shigeru Hashimoto¹, Tohru Tsujimura², Masaki Morishige^1, 3, Ari Hashimoto¹, Kosuke Aritake⁴, Atsuko Yamada¹, Jin-Min Nam¹, Hiroshi Kiyonari⁵, Kazuki Nakao⁵ & Hisataka Sabe^1, 6

¹  Department of Molecular Biology, Osaka Bioscience Institute, Suita 565-0874, Japan.

²  Department of Pathology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.

³  Department of Neurosurgery, School of Medicine, Oita University, Oita 879-5593, Japan.

⁴  Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita 565-0874, Japan.

⁵  Laboratory for Animal Resources and Genetic Engineering, Center for Developmental Biology, RIKEN Kobe, Kobe 650-0047, Japan.

⁶  Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.

In neutrophils, superoxide anion production generally accompanies chemotaxis and functions in killing invading pathogens. The GIT2 GTPase-activating protein binds to the guanine nucleotide–exchange factor PIX. Here we show that GIT2 was necessary for directional chemotaxis and for the suppression of superoxide production in G protein–coupled receptor–stimulated neutrophils. GIT2 was also necessary for the orientation of superoxide production toward chemoattractant sources. GIT2 suppressed the activity of ADP ribosylation factor 1 and was a component of the G subunit–mediated direction-sensing machinery 'downstream' of G protein–coupled receptor signaling. This study establishes a function for GIT2 in linking chemotaxis and superoxide production in neutrophils and shows that loss of GIT2 in vivo leads to an immunodeficient state.

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