The chemokine ESkine/CCL27 displays novel modes of intracrine and paracrine function
The chemokine ESkine/CCL27 displays novel modes of intracrine and paracrine function
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DOI：
10.4049/jimmunol.169.3.1387
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发表时间：
2002-08-01
影响因子：
4.4
通讯作者：
Graham, GJ
中科院分区：
文献类型：
--
作者：
Gortz, A;Nibbs, RJB;Graham, GJ
我们之前已经表明，β-趋化因子ESkine/CCL 27差异剪接产生两种替代形式。一种是分泌的趋化因子（ESkine），而另一种（PESKY）缺乏信号肽，并被易位到细胞核。这种核靶向趋化因子的作用迄今尚未确定，本研究的目的是更深入地研究这种趋化因子变体。为了鉴定参与核转位的PESKY区域，我们用增强型绿色荧光蛋白标记片段并在中国仓鼠卵巢细胞中表达。我们显示PESKY核转位依赖于与信号肽携带变体ESkine共享的C-末端残基。事实上，我们进一步证明，ESkine也可以使用这些C-末端残基进入细胞核后受体（CCR 10）介导的内化。为了研究PESKY的生物学作用，我们在3 T3细胞中过表达它。这种过度表达导致显著的细胞骨架重排，这与细胞肌动蛋白细胞骨架的彻底重组一致。微阵列分析和抗体中和研究表明，这些变化部分介导的胰岛素样生长因子-1。此外，单层创伤试验表明PESKY表达与显著增加的迁移能力相关。因此，我们认为核PESKY和ESkine都通过内分泌或旁分泌机制进入细胞核，并可能通过诱导肌动蛋白细胞骨架松弛促进细胞迁移。因此，核ESkine/PESKY代表了趋化因子功能的新范式。
We have previously shown that the beta-chemokine ESkine/CCL27 is differentially spliced to produce two alternative forms. One is a secreted chemokine (ESkine), whereas the other (PESKY) lacks a signal peptide and is translocated to the nucleus. The role of this nuclear-targeted chemokine has not so far been defined, and it was the purpose of this study to examine this chemokine variant in more depth. To identify the region of PESKY involved in the nuclear translocation we tagged fragments with enhanced green fluorescent protein and expressed them in Chinese hamster ovary cells. We show PESKY nuclear translocation to be dependent on C-terminal residues that are shared with the signal peptide-bearing variant ESkine. Indeed we further demonstrate that ESkine can also use these C-terminal residues to enter the nucleus of cells following receptor (CCR10)-mediated internalization. To examine biological roles for PESKY we have overexpressed it in 3T3 cells. Such overexpression results in marked cytoskeletal rearrangements that are coincident with a radical reorganization of the cellular actin cytoskeleton. Microarray analyses and Ab neutralization studies indicate that these changes are mediated in part by insulin-like growth factor-1. Furthermore, monolayer wounding assays indicate that PESKY expression correlates with markedly increased migratory capacity. Thus, it is our contention that nuclear PESKY and ESkine both enter the nucleus by either intracrine or paracrine mechanisms and may facilitate cellular migration by inducing actin cytoskeletal relaxation. Therefore, nuclear ESkine/PESKY represents a novel paradigm for chemokine function.