<br>Ring Finger Protein 11 通过与 ANKRD13 蛋白家族的 UIM 区域直接相互作用，作用于配体激活的 EGFR。,The FEBS Journal

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Ring Finger Protein 11 通过与 ANKRD13 蛋白家族的 UIM 区域直接相互作用，作用于配体激活的 EGFR。
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-01-27 , DOI: 10.1111/febs.15226
Anna Mattioni ₁ , Karsten Boldt ₂ , Giulio Auciello ₃ , Masayuki Komada ₄ , Joshua Z Rappoport ₅ , Marius Ueffing ₂ , Luisa Castagnoli ₁ , Gianni Cesareni _{1,

6} , Elena Santonico ₁

Affiliation

RING Finger Protein 11 (RNF11) 是一种进化保守的、真正有趣的新基因 E3 连接酶，在多种人类肿瘤中过度表达。尽管一些报告强调了它参与关键的细胞过程，但其功能背后的机制细节仍然知之甚少。利用基于培养物氨基酸稳定同位素标记 (SILAC) 的蛋白质组学分析，我们鉴定了 51 种与野生型 RNF11 和/或其催化失活突变体共免疫沉淀的蛋白质。我们将注意力集中在 RNF11 与含有锚蛋白重复结构域的蛋白 13 (ANKRD13) 家族的相互作用上。 ANKRD13 家族的成员包含泛素相互作用基序 (UIM)，可识别配体结合后不久附加到表皮生长因子受体 (EGFR) 的 Lys-63 连接泛素 (Ub) 链。我们发现 ANKRD13A、ANKRD13B 和 ANKRD13D在体内与 RNF11 形成复合物，并且 UIM 是复合物形成所必需的。然而，与传统的 UIM 结合模式不同，RNF11 的 Ub 修饰并不是与 ANKRD13 蛋白相互作用所必需的。我们还表明，ANKRD13A 和 RNF11 之间的相互作用受到 EGF 刺激的调节，并且由 ANKRD13A、RNF11 和激活的 EGFR 形成的复合物在受体内吞作用的早期阶段短暂组装。此外，E3 连接酶 Itchy E3 泛素蛋白连接酶 (ITTCH) 或 RNF11 的功能丧失分别会消除或增加内源性 ANKRD13A 的泛素化，影响其结合活化 EGFR 的能力。我们提出了一个模型，其中 ANKRD13 蛋白充当分子支架，促进激活的 EGFR 与 E3 连接酶 ITCH 和 RNF11 之间复合物的瞬时形成。通过调节 ANKRD13A 的泛素化状态及其内吞接头功能，RNF11 促进激活的 EGFR 的分选以进行溶酶体降解。

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Ring Finger Protein 11 acts on ligand-activated EGFR via the direct interaction with the UIM region of ANKRD13 protein family.

RING finger protein 11 (RNF11) is an evolutionary conserved Really Interesting New Gene E3 ligase that is overexpressed in several human tumours. Although several reports have highlighted its involvement in crucial cellular processes, the mechanistic details underlying its function are still poorly understood. Utilizing stable isotope labelling by amino acids in culture (SILAC)‐based proteomics analysis, we identified 51 proteins that co‐immunoprecipitate with wild‐type RNF11 and/or with its catalytically inactive mutant. We focused our attention on the interaction of RNF11 with Ankyrin repeat domain‐containing protein 13 (ANKRD13)s family. Members of the ANKRD13 family contain ubiquitin‐interacting motifs (UIM) that recognize the Lys‐63‐linked ubiquitin (Ub) chains appended to Epidermal growth factor receptor (EGFR) soon after ligand binding. We show that ANKRD13A, ANKRD13B and ANKRD13D form a complex with RNF11 in vivo and that the UIMs are required for complex formation. However, at odds with the conventional UIM binding mode, Ub modification of RNF11 is not required for the interaction with ANKRD13 proteins. We also show that the interaction between ANKRD13A and RNF11 is modulated by the EGF stimulus and that a complex formed by ANKRD13A, RNF11 and activated EGFR is transiently assembled in the early phases of receptor endocytosis. Moreover, loss of function of the E3 ligases Itchy E3 ubiquitin‐protein ligase (ITCH) or RNF11, respectively, abrogates or increases the ubiquitination of endogenous ANKRD13A, affecting its ability to bind activated EGFR. We propose a model whereby the ANKRD13 proteins act as molecular scaffolds that promote the transient formation of a complex between the activated EGFR and the E3 ligases ITCH and RNF11. By regulating the ubiquitination status of ANKRD13A and consequently its endocytic adaptor function, RNF11 promotes sorting of the activated EGFR for lysosomal degradation.

更新日期：2020-01-27

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