DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses
| Autor: | Yoshihiko Tanaka, Yosuke Harada, Tomoya Katakai, Masao Terasawa, Mikako Shirouzu, Mutsuko Kukimoto-Niino, Tatsuo Kinashi, Shigeyuki Yokoyama, Tomoko Nishizaki, Fumiyuki Sanematsu, Markus Pieczyk, Yoshinori Fukui, Kyoko Hanawa-Suetsugu, Akihiko Nishikimi, Takehito Uruno, Xuefeng Duan, Jens V. Stein, Katsuyoshi Habiro |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Immunology Cell Culture Techniques Leading edge membrane CDC42 Biology Adaptive Immunity Biochemistry Extracellular matrix 03 medical and health sciences Mice 0302 clinical medicine Cell Movement Animals Guanine Nucleotide Exchange Factors Humans Dendritic cell migration cdc42 GTP-Binding Protein Cells Cultured 030304 developmental biology Immunobiology Mice Knockout 0303 health sciences Cell Biology Hematology Dendritic Cells Acquired immune system Cell biology Mice Inbred C57BL HEK293 Cells Cdc42 GTP-Binding Protein Female Guanine nucleotide exchange factor Dock8 030215 immunology |
| Zdroj: | Blood |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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