title: DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses.
abstract: 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.
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Harada
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masao
authors.initials: M
authors.lastname: Terasawa
authors.forename: Markus
authors.initials: M
authors.lastname: Pieczyk
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Habiro
authors.forename: Tomoya
authors.initials: T
authors.lastname: Katakai
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hanawa-Suetsugu
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Kukimoto-Niino
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishizaki
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Duan
authors.forename: Takehito
authors.initials: T
authors.lastname: Uruno
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nishikimi
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sanematsu
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Jens V
authors.initials: JV
authors.lastname: Stein
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kinashi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics* / Q000276:immunology; D000818:Animals; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism / Q000502:physiology*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D020764:cdc42 GTP-Binding Protein