The MIT domain of UBPY constitutes a CHMP binding and endosomal localization signal required for efficient epidermal growth factor receptor degradation
The MIT domain of UBPY constitutes a CHMP binding and endosomal localization signal required for efficient epidermal growth factor receptor degradation
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DOI：
10.1074/jbc.m704009200
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发表时间：
2007-10-19
影响因子：
4.8
通讯作者：
Urbe, Sylvie
中科院分区：
文献类型：
--
作者：
Row, Paula E.;Liu, Han;Urbe, Sylvie
我们在去泛素化酶UBPY/USP8的N端鉴定并表征了一个微管相互作用和运输（MIT）结构域。与其他含有MIT的蛋白如AMSH和VPS4一样，UBPY可以与CHMP蛋白相互作用，CHMP蛋白调节泛素化受体的内体分选。比较UBPY MIT结构域与另一种泛素异肽酶AMSH对人类CHMP家族11个成员的结合偏好，发现与CHMP1A和CHMP1B有共同的相互作用，但AMSH对ESCRT-III复合体的核心亚基CHMP3/VPS24和UBPY对CHMP7有明显的选择性。我们还表明，与AMSH一样，UBPY去泛素化酶活性可以被STAM刺激，但对其同源chmp没有反应。UBPY MIT结构域对于其催化活性是必不可少的，但对于其定位到核内体是必不可少的。这在功能上是重要的，因为mit缺失的UBPY突变体无法从蛋白酶体降解中拯救其结合伴侣STAM，也无法逆转小干扰rna介导的UBPY缺失对表皮生长因子受体降解造成的阻滞。
We have identified and characterized a Microtubule Interacting and Transport (MIT) domain at the N terminus of the deubiquitinating enzyme UBPY/USP8. In common with other MIT containing proteins such as AMSH and VPS4, UBPY can interact with CHMP proteins, which are known to regulate endosomal sorting of ubiquitinated receptors. Comparison of binding preferences for the 11 members of the human CHMP family between the UBPY MIT domain and another ubiquitin isopeptidase, AMSH, reveals common interactions with CHMP1A and CHMP1B but a distinct selectivity of AMSH for CHMP3/VPS24, a core subunit of the ESCRT-III complex, and UBPY for CHMP7. We also show that in common with AMSH, UBPY deubiquitinating enzyme activity can be stimulated by STAM but is unresponsive to its cognate CHMPs. The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. This is functionally significant as an MIT-deleted UBPY mutant is unable to rescue its binding partner STAM from proteasomal degradation or reverse a block to epidermal growth factor receptor degradation imposed by small interfering RNA-mediated depletion of UBPY.