DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses

Yosuke Harada, Yoshihiko Tanaka, Masao Terasawa, Markus Pieczyk, Katsuyoshi Habiro, Tomoya Katakai, Hanawa Suetsugu Kyoko, Kukimoto Niino Mutsuko, Tomoko Nishizaki, Mikako Shirouzu, Xuefeng Duan, Takehito Uruno, Akihiko Nishikimi, Fumiyuki Sanematsu, Shigeyuki Yokoyama, Jens V. Stein, Tatsuo Kinashi, Yoshinori Fukui

研究成果: Contribution to journalArticle査読

152 被引用数 (Scopus)

抄録

To migrate efficiently through the interstitium, dendritic cells (DCs) constantly adapt their shape to the given structure of the extracellular matrix and follow the path of least resistance. It is known that this amoeboid migration of DCs requires Cdc42, yet the upstream regulators critical for localization and activation of Cdc42 remain to be determined. Mutations of DOCK8, a member of the atypical guanine nucleotide exchange factor family, causes combined immunodeficiency in humans. In the present study, we show that DOCK8 is a Cdc42-specific guanine nucleotide exchange factor that is critical for interstitial DC migration. By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming. Although DOCK8-deficient DCs migrated normally on 2-dimensional surfaces, DOCK8 was required for DCs to crawl within 3-dimensional fibrillar networks and to transmigrate through the subcapsular sinus floor. This function of DOCK8 depended on the DHR-2 domain mediating Cdc42 activation. DOCK8 deficiency did not affect global Cdc42 activity. However, Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration. Therefore, DOCK8 regulates interstitial DC migration by controlling Cdc42 activity spatially.

本文言語英語
ページ(範囲)4451-4461
ページ数11
ジャーナルBlood
119
19
DOI
出版ステータス出版済み - 5 10 2012

All Science Journal Classification (ASJC) codes

  • 生化学
  • 免疫学
  • 血液学
  • 細胞生物学

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