DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses
DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses
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DOI：
10.1182/blood-2012-01-407098
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发表时间：
2012-05-10
期刊：
影响因子：
20.3
通讯作者：
Fukui, Yoshinori
中科院分区：
文献类型：
--
作者：
Harada, Yosuke;Tanaka, Yoshihiko;Fukui, Yoshinori
为了有效地迁移通过树突状细胞，树突状细胞（DC）不断地使其形状适应细胞外基质的给定结构，并遵循阻力最小的路径。已知DC的这种变形虫样迁移需要Cdc 42，但对Cdc 42的定位和激活至关重要的上游调节因子仍有待确定。DOCK 8是非典型鸟嘌呤核苷酸交换因子家族的成员，其突变导致人类联合免疫缺陷。在本研究中，我们发现DOCK 8是一种Cdc 42特异性鸟嘌呤核苷酸交换因子，对间质性DC迁移至关重要。通过产生敲除小鼠，我们发现在DOCK 8不存在的情况下，DC不能在淋巴结实质中积累用于T细胞引发。虽然DOCK 8缺陷的DC在二维表面上正常迁移，但DC在三维纤维网络内爬行并穿过被膜下窦底需要DOCK 8。DOCK 8的这种功能依赖于DHR-2结构域介导Cdc 42激活。DOCK 8缺乏并不影响全球Cdc 42活性。然而，Cdc 42激活的前缘膜受损DOCK 8缺陷的DC，导致严重缺陷变形虫极化和迁移。因此，DOCK 8通过在空间上控制Cdc 42活性来调节间质DC迁移。（血。2012;119（19）：4451-4461）
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. (Blood. 2012;119(19):4451-4461)