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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >The full-length interleukin-33 (FLIL33)–importin-5 interaction does not regulate nuclear localization of FLIL33 but controls its intracellular degradation
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The full-length interleukin-33 (FLIL33)–importin-5 interaction does not regulate nuclear localization of FLIL33 but controls its intracellular degradation

机译：全长白介素33（FLIL33）–importin-5相互作用不调节FLIL33的核定位但控制其细胞内降解

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摘要

Human mature IL-33 is a member of the IL-1 family and a potent regulator of immunity through its pro-T helper cell 2 activity. Its precursor form, full-length interleukin-33 (FLIL33), is an intranuclear protein in many cell types, including fibroblasts, and its intracellular levels can change in response to stimuli. However, the mechanisms controlling the nuclear localization of FLIL33 or its stability in cells are not understood. Here, we identified importin-5 (IPO5), a member of the importin family of nuclear transport proteins, as an intracellular binding partner of FLIL33. By overexpressing various FLIL33 protein segments and variants in primary human lung fibroblasts and HEK293T cells, we show that FLIL33, but not mature interleukin-33, physically interacts with IPO5 and that this interaction localizes to a cluster of charged amino acids (positions 46–56) but not to an adjacent segment (positions 61–67) in the FLIL33 N-terminal region. siRNA-mediated IPO5 knockdown in cell culture did not affect nuclear localization of FLIL33. However, the IPO5 knockdown significantly decreased the intracellular levels of overexpressed FLIL33, reversed by treatment with the 20S proteasome inhibitor bortezomib. Furthermore, FLIL33 variants deficient in IPO5 binding remained intranuclear and exhibited decreased levels, which were also restored by the bortezomib treatment. These results indicate that the interaction between FLIL33 and IPO5 is localized to a specific segment of the FLIL33 protein, is not required for nuclear localization of FLIL33, and protects FLIL33 from proteasome-dependent degradation.
机译：人类成熟的IL-33是IL-1家族的成员，并且是通过其pro-T辅助细胞2活性而有效调节免疫力的。它的前体形式全长白介素33（FLIL33）是许多细胞类型（包括成纤维细胞）中的一种核内蛋白，其细胞内水平可以响应刺激而发生变化。然而，尚不清楚控制FLIL33的核定位或其在细胞中稳定性的机制。在这里，我们确定了importin-5（IPO5），其是核转运蛋白importin家族的成员，是FLIL33的细胞内结合伴侣。通过在原代人肺成纤维细胞和HEK293T细胞中过表达各种FLIL33蛋白区段和变体，我们显示出FLIL33（而非成熟的白介素33）与IPO5发生物理相互作用，并且这种相互作用定位于带电荷的氨基酸簇（位置46-56） ），但不在FLIL33 N端区域的相邻片段（61-67位）上。 siRNA介导的细胞培养中的IPO5敲低并不影响FLIL33的核定位。然而，通过用20S蛋白酶体抑制剂硼替佐米治疗，IPO5敲低显着降低了过表达FLIL33的细胞内水平。此外，缺乏IPO5结合的FLIL33变体仍保留在核内并显示出降低的水平，这也通过硼替佐米治疗得以恢复。这些结果表明，FLIL33和IPO5之间的相互作用被定位到FLIL33蛋白的特定部分，对于FLIL33的核定位不是必需的，并且可以保护FLIL33不受蛋白酶体依赖性降解。

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