The HECT ubiquitin ligase AIP4 regulates the cell surface expression of select TRP channels
The HECT ubiquitin ligase AIP4 regulates the cell surface expression of select TRP channels
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DOI：
10.1038/sj.emboj.7601429
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发表时间：
2006-12-13
期刊：
影响因子：
11.4
通讯作者：
Walz, Gerd
中科院分区：
文献类型：
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作者：
Wegierski, Tomasz;Hill, Kerstin;Walz, Gerd
TRPV4是瞬时受体电位(TRP)家族中广泛表达的成员，它促进钙离子进入非兴奋性细胞。TRPV4被几种刺激激活，但该通道的活动是如何终止的在很大程度上尚不清楚。在这里，我们表明泛素化是控制TRPV4在质膜上存在的一个重要机制。TRPV4的泛素化被Hect(与E6-AP羧基末端同源)家族泛素连接酶AIP4显著增加，而不会导致这一通道的降解。相反，AIP4促进TRPV4的内吞作用，并减少其在质膜上的数量。因此，尽管TRPV4水平总体上升，但TRPV4的基础活性降低。这种监管模式并不局限于TRPV4。TRPC4是Trp通道家族的另一个成员，在AIP4存在的情况下，TRPC4也被高度泛素化，导致TRPC4在细胞内的定位增加，其基础活性降低。然而，其他几个Trp通道的泛素化不受AIP4的影响，这表明AIP4介导的调节是特定Trp通道的独特特性。
TRPV4 is a widely expressed member of the transient receptor potential (TRP) family that facilitates Ca2+ entry into nonexcitable cells. TRPV4 is activated by several stimuli, but it is largely unknown how the activity of this channel is terminated. Here, we show that ubiquitination represents an important mechanism to control the presence of TRPV4 at the plasma membrane. Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane. Consequently, the basal activity of TRPV4 is reduced despite an overall increase in TRPV4 levels. This mode of regulation is not limited to TRPV4. TRPC4, another member of the TRP channel family, is also strongly ubiquitinated in the presence of AIP4, leading to the increased intracellular localization of TRPC4 and the reduction of its basal activity. However, ubiquitination of several other TRP channels is not affected by AIP4, demonstrating that AIP4-mediated regulation is a unique property of select TRP channels.