Investigations into the auto-FAT10ylation of the bispecific E2 conjugating enzyme UBA6-specific E2 enzyme 1
Investigations into the auto-FAT10ylation of the bispecific E2 conjugating enzyme UBA6-specific E2 enzyme 1
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DOI：
10.1111/febs.12745
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发表时间：
2014-04-01
期刊：
影响因子：
5.4
通讯作者：
Groettrup, Marcus
中科院分区：
文献类型：
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作者：
Aichem, Annette;Catone, Nicola;Groettrup, Marcus
腺嘌呤诱导的泛素样修饰剂HLA-F邻近转录物10（FAT 10）靶向其底物，以被蛋白酶体降解。FAT 10通过双特异性泛素活化酶和FAT 10活化酶UBA 6、同样的双特异性缀合酶UBA 6特异性E2酶1（USE 1）和可能的E3连接酶与其底物缀合。通过质谱分析，我们发现USE 1在Lys 323处发生了自身脂肪酸10基化。Lys 323突变为精氨酸并没有消除USE 1的自身FAT 10化，但每隔一个赖氨酸都可以用FAT 10修饰。与大量FAT 10底物类似，USE 1的FAT 10化加速了其蛋白酶体降解。有趣的是，USE 1-FAT 10缀合物仍然是活性E2酶，因为FAT 10和泛素两者仍然可以与USE 1-FAT 10缀合物硫酯连接。因此，我们认为USE 1自身FAT 10化的主要功能是作为一种负反馈机制，通过蛋白酶体降解USE 1-FAT 10缀合物来减少USE 1的量，从而限制FAT 10在细胞因子介导的诱导下的缀合。结构化数字摘要中心点withby（）中心点withby（）
The cytokine-inducible ubiquitin-like modifier HLA-F adjacent transcript10 (FAT10) targets its substrates for degradation by the proteasome. FAT10 is conjugated to its substrates via the bispecific, ubiquitin-activating and FAT10-activating enzyme UBA6, the likewise bispecific conjugating enzyme UBA6-specific E2 enzyme 1 (USE1), and possibly E3 ligases. By MS analysis, we found that USE1 undergoes self-FAT10ylation incis, mainly at Lys323. Mutation of Lys323 to an arginine did not abolish auto-FAT10ylation of USE1, but every other lysine could instead be modified with FAT10. Similarly to bulk FAT10 substrates, FAT10ylation of USE1 accelerated its proteasomal degradation. Interestingly, the USE1-FAT10 conjugate continued to be an active E2 enzyme, because both FAT10 and ubiquitin could still be thioester-linked to the USE1-FAT10 conjugate. We therefore suggest that the major function of USE1 auto-FAT10ylation is to serve as a negative feedback mechanism to limit the conjugation of FAT10 upon its cytokine-mediated induction by reducing the amount of USE1 through proteasomal degradation of the USE1-FAT10 conjugate.Structured digital abstract center dot withby()center dot withby()