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Tankyrase regulates epithelial lumen formation via suppression of Rab11 GEFs
Journal of Cell Biology ( IF 7.4 ) Pub Date : 2021-06-15 , DOI: 10.1083/jcb.202008037
Arun A Chandrakumar 1, 2 , Étienne Coyaud 2 , Christopher B Marshall 2 , Mitsuhiko Ikura 1, 2 , Brian Raught 1, 2 , Robert Rottapel 1, 2, 3, 4
Affiliation  

Rab11 GTPase proteins are required for cytokinesis, ciliogenesis, and lumenogenesis. Rab11a is critical for apical delivery of podocalyxin (PODXL) during lumen formation in epithelial cells. SH3BP5 and SH3BP5L are guanine nucleotide exchange factors (GEFs) for Rab11. We show that SH3BP5 and SH3BP5L are required for activation of Rab11a and cyst lumen formation. Using proximity-dependent biotin identification (BioID) interaction proteomics, we have identified SH3BP5 and its paralogue SH3BP5L as new substrates of the poly-ADP-ribose polymerase Tankyrase and the E3 ligase RNF146. We provide data demonstrating that epithelial polarity via cyst lumen formation is governed by Tankyrase, which inhibits Rab11a activation through the suppression of SH3BP5 and SH3BP5L. RNF146 reduces Tankyrase protein abundance and restores Rab11a activation and lumen formation. Thus, Rab11a activation is controlled by a signaling pathway composed of the sequential inhibition of SH3BP5 paralogues by Tankyrase, which is itself suppressed by RNF146.

中文翻译:

端锚聚合酶通过抑制 Rab11 GEF 调节上皮腔形成

Rab11 GTPase 蛋白是胞质分裂、纤毛发生和管腔发生所必需的。Rab11a 对于上皮细胞管腔形成过程中足萼蛋白 (PODXL) 的顶端递送至关重要。SH3BP5 和 SH3BP5L 是 Rab11 的鸟嘌呤核苷酸交换因子 (GEF)。我们发现 SH3BP5 和 SH3BP5L 是 Rab11a 激活和囊腔形成所必需的。利用邻近依赖性生物素识别 (BioID) 相互作用蛋白质组学,我们已将 SH3BP5 及其旁系同源物 SH3BP5L 鉴定为聚 ADP 核糖聚合酶 Tankyrase 和 E3 连接酶 RNF146 的新底物。我们提供的数据表明,通过囊腔形成的上皮极性是由端锚聚合酶控制的,端锚聚合酶通过抑制 SH3BP5 和 SH3BP5L 来抑制 Rab11a 激活。RNF146 降低端锚聚合酶蛋白丰度并恢复 Rab11a 激活和管腔形成。因此,Rab11a 的激活是由一条信号通路控制的,该信号通路由 Tankyrase 对 SH3BP5 旁系同源物的连续抑制组成,而 Tankyrase 本身又被 RNF146 抑制。
更新日期:2021-06-15
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