Hematopoietic lineage cell-specific protein 1 functions in concert with the Wiskott-Aldrich syndrome protein to promote podosome array organization and chemotaxis in dendritic cells.
Hematopoietic lineage cell-specific protein 1 functions in concert with the Wiskott-Aldrich syndrome protein to promote podosome array organization and chemotaxis in dendritic cells.
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造血谱系细胞特异性蛋白 1 与 Wiskott-Aldrich 综合征蛋白协同作用，促进树突状细胞中的足小体阵列组织和趋化性。
DOI：
10.4049/jimmunol.1003102
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发表时间：
2011-04-15
期刊：
影响因子：
--
通讯作者：
Burkhardt JK
中科院分区：
文献类型：
--
作者：
Dehring DA;Clarke F;Ricart BG;Huang Y;Gomez TS;Williamson EK;Hammer DA;Billadeau DD;Argon Y;Burkhardt JK
树突状细胞（Dendritic cells，DC）是一种专职的APC，其存在于外周组织中并检测机体的病原体。在被炎症信号激活后，DC经历成熟过程并迁移到淋巴器官，在那里它们将病原体来源的Ag呈递给T细胞。DC迁移依赖于肌动蛋白细胞骨架的严格调节，以允许快速适应环境线索。我们研究了造血谱系细胞特异性蛋白1（HS 1），皮质激素的造血同源物，在调节小鼠树突状细胞的肌动蛋白细胞骨架的作用。HS 1定位于板状伪足突起和足体，与粘附和迁移相关的富含肌动蛋白的结构。来自HS 1 −/−小鼠的DC表现出异常的板层脂质动力学。此外，虽然这些细胞形成可识别的podosomes，他们的podosomes阵列是松散的包装和不正确的定位在细胞内。HS 1与Wiskott-Aldrich综合征蛋白（WASp）相互作用，WASp是另一种关键的肌动蛋白调节蛋白，通过与WASp相互作用蛋白相互结合。对HS 1、WASp或这两种蛋白质缺陷的DC的比较分析揭示了这些蛋白质在调节粒体方面的独特作用，其中WASp对于粒体形成至关重要，而HS 1确保了有效的阵列组织。WASp的招聘到podosome核心是独立的HS 1，而HS 1招聘需要Src同源3结构域依赖的WASp/WASp相互作用蛋白异二聚体的相互作用。在迁移试验中，HS 1和WASP缺陷型DC的表型相关，但不同。在趋化因子梯度中迁移的WASp−/y DCs表现出速度的大幅下降和方向持久性的减弱。相比之下，HS 1 −/− DC迁移速度比野生型细胞快，但方向持久性显着降低。这些研究表明，HS 1与WASp协同作用，以微调DC细胞结构并指导细胞迁移。
Dendritic cells (DCs) are professional APCs that reside in peripheral tissues and survey the body for pathogens. Upon activation by inflammatory signals, DCs undergo a maturation process and migrate to lymphoid organs, where they present pathogen-derived Ags to T cells. DC migration depends on tight regulation of the actin cytoskeleton to permit rapid adaptation to environmental cues. We investigated the role of hematopoietic lineage cell-specific protein 1 (HS1), the hematopoietic homolog of cortactin, in regulating the actin cytoskeleton of murine DCs. HS1 localized to lamellipodial protrusions and podosomes, actin-rich structures associated with adhesion and migration. DCs from HS1−/− mice showed aberrant lamellipodial dynamics. Moreover, although these cells formed recognizable podosomes, their podosome arrays were loosely packed and improperly localized within the cell. HS1 interacts with Wiskott-Aldrich Syndrome protein (WASp), another key actin-regulatory protein, through mutual binding to WASp-interacting protein. Comparative analysis of DCs deficient for HS1, WASp or both proteins revealed unique roles for these proteins in regulating podosomes with WASp being essential for podosome formation and with HS1 ensuring efficient array organization. WASp recruitment to podosome cores was independent of HS1, whereas HS1 recruitment required Src homology 3 domain-dependent interactions with the WASp/WASp-interacting protein heterodimer. In migration assays, the phenotypes of HS1- and WASp-deficient DCs were related, but distinct. WASp−/y DCs migrating in a chemokine gradient showed a large decrease in velocity and diminished directional persistence. In contrast, HS1−/− DCs migrated faster than wild-type cells, but directional persistence was significantly reduced. These studies show that HS1 functions in concert with WASp to fine-tune DC cytoarchitecture and direct cell migration.
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影响因子：
9.2
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