Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth factor and chemokine receptors destined for lysosomal degradation
Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth factor and chemokine receptors destined for lysosomal degradation
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DOI：
10.1111/j.1600-0854.2007.00630.x
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发表时间：
2007-11-01
期刊：
影响因子：
4.5
通讯作者：
Stenmark, Harald
中科院分区：
文献类型：
--
作者：
Malerod, Lene;Stuffers, Susanne;Stenmark, Harald
泛素结合蛋白HRs和转运所需的内体分选复合体(ESCRT)-I和ESCRT-III参与将内吞和泛素化的受体分选到溶酶体，以降解和有效终止信号。在这项研究中，我们研究了ESCRT-II亚单位Vps22/EAP30在泛素化受体降解性蛋白质分类中的作用。Vps22在HeLa细胞中瞬时表达，在含有内吞的表皮生长因子受体(EGFR)以及HRs、ESCRT-I和ESCRT-III的内体中检测到。通过小干扰RNA耗尽Vps22，伴随着其他ESCRT-II亚单位水平的下降，极大地减少了EGFR及其配体EGF以及趋化因子受体CXCR4的降解。在Vps22缺失的细胞中，EGFR聚集在早期内体和异常小的多泡小体的限制膜上。HRs或ESCRT-I亚单位Tsg101的缺失维持了EGF激活受体下游细胞外信号调节的Kase1/2的磷酸化和核转位。相比之下，当Vps22耗尽时，情况并非如此。这些结果表明Vps22在配体诱导的EGFR和CXCR4转换中起重要作用，并提示EGF信号的终止发生在ESCRT-II参与之前。
The ubiquitin-binding protein Hrs and endosomal sorting complex required for transport (ESCRT)-I and ESCRT-III are involved in sorting endocytosed and ubiquitinated receptors to lysosomes for degradation and efficient termination of signaling. In this study, we have investigated the role of the ESCRT-II subunit Vps22/EAP30 in degradative protein sorting of ubiquitinated receptors. Vps22 transiently expressed in HeLa cells was detected in endosomes containing endocytosed epidermal growth factor receptors (EGFRs) as well as Hrs and ESCRT-I and ESCRT-III. Depletion of Vps22 by small interfering RNA, which was accompanied by decreased levels of other ESCRT-II subunits, greatly reduced degradation of EGFR and its ligand EGF as well as the chemokine receptor CXCR4. EGFR accumulated on the limiting membranes of early endosomes and aberrantly small multivesicular bodies in Vps22-depleted cells. Phosphorylation and nuclear translocation of extracellular-signal-regulated kinase1/2 downstream of the EGF-activated receptor were sustained by depletion of Hrs or the ESCRT-I subunit Tsg101. In contrast, this was not the case when Vps22 was depleted. These results indicate an important role for Vps22 in ligand-induced EGFR and CXCR4 turnover and suggest that termination of EGF signaling occurs prior to ESCRT-II engagement.