Hax-1 is rapidly degraded by the proteasome dependent on its PEST sequence.
Hax-1 is rapidly degraded by the proteasome dependent on its PEST sequence.
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DOI：
10.1186/1471-2121-13-20
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发表时间：
2012-07-24
期刊：
影响因子：
--
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Li B;Hu Q;Xu R;Ren H;Fei E;Chen D;Wang G
HS-1相关蛋白X-1（Hax-1）是与Bcl-2家族成员具有序列同源性的多功能蛋白。HAX-1基因敲除的动物表明，它在中枢神经系统中对各种压力起着重要的保护作用。HAX-1基因纯合突变与常染色体隐性形式的重度先天性中性粒细胞减少症沿着神经系统症状相关。Hax-1的蛋白水平已被证明是由细胞蛋白酶切割或刺激后的转录抑制调节。在这里，我们报告了一种新的翻译后机制，调节Hax-1在哺乳动物细胞中的水平。我们发现，PEST序列，一个富含脯氨酸，谷氨酸，丝氨酸和苏氨酸的序列，负责其多聚泛素化和快速降解。Hax-1与K48连接的泛素链结合，并通过蛋白酶体系统进行快速周转。缺失PEST序列的Hax-1的缺失突变体比野生型Hax-1更能抵抗蛋白酶体降解，并对凋亡刺激发挥更大的保护作用。我们的数据表明，Hax-1是一种短寿命的蛋白质，其PEST序列依赖性蛋白酶体的快速降解可能有助于不同刺激后的快速细胞反应。
HS-1-associated protein X-1 (Hax-1), is a multifunctional protein that has sequence homology to Bcl-2 family members. HAX-1 knockout animals reveal that it plays an essential protective role in the central nervous system against various stresses. Homozygous mutations in the HAX-1 gene are associated with autosomal recessive forms of severe congenital neutropenia along with neurological symptoms. The protein level of Hax-1 has been shown to be regulated by cellular protease cleavage or by transcriptional suppression upon stimulation. Here, we report a novel post-translational mechanism for regulation of Hax-1 levels in mammalian cells. We identified that PEST sequence, a sequence rich in proline, glutamic acid, serine and threonine, is responsible for its poly-ubiquitination and rapid degradation. Hax-1 is conjugated by K48-linked ubiquitin chains and undergoes a fast turnover by the proteasome system. A deletion mutant of Hax-1 that lacks the PEST sequence is more resistant to the proteasomal degradation and exerts more protective effects against apoptotic stimuli than wild type Hax-1. Our data indicate that Hax-1 is a short-lived protein and that its PEST sequence dependent fast degradation by the proteasome may contribute to the rapid cellular responses upon different stimulations.
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DOI：
10.1016/j.bbrc.2010.02.084
发表时间：
2010-03-19
影响因子：
3.1
作者：
Kang, Young Ji;Jang, Mi;Park, Sung Goo
通讯作者：
Park, Sung Goo
影响因子：
5.4
作者：
Kawaguchi, Y;Nakajima, K;Hirai, K
通讯作者：
Hirai, K
影响因子：
4.8
作者：
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影响因子：
56.9
作者：
ROGERS, S;WELLS, R;RECHSTEINER, M
通讯作者：
RECHSTEINER, M
影响因子：
3.5
作者：
Grzybowska, EA;Sarnowska, E;Siedlecki, JA
通讯作者：
Siedlecki, JA