Wunderle Lina, Knopf Julia D, Kühnle Nathalie, Morlé Aymeric, Hehn Beate, Adrain Colin, Strisovsky Kvido, Freeman Matthew, Lemberg Marius K
Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Sci Rep. 2016 Jun 6;6:27342. doi: 10.1038/srep27342.
Rhomboid intramembrane proteases are the enzymes that release active epidermal growth factor receptor (EGFR) ligands in Drosophila and C. elegans, but little is known about their functions in mammals. Here we show that the mammalian rhomboid protease RHBDL4 (also known as Rhbdd1) promotes trafficking of several membrane proteins, including the EGFR ligand TGFα, from the endoplasmic reticulum (ER) to the Golgi apparatus, thereby triggering their secretion by extracellular microvesicles. Our data also demonstrate that RHBDL4-dependent trafficking control is regulated by G-protein coupled receptors, suggesting a role for this rhomboid protease in pathological conditions, including EGFR signaling. We propose that RHBDL4 reorganizes trafficking events within the early secretory pathway in response to GPCR signaling. Our work identifies RHBDL4 as a rheostat that tunes secretion dynamics and abundance of specific membrane protein cargoes.
菱形膜内蛋白酶是在果蝇和秀丽隐杆线虫中释放活性表皮生长因子受体（EGFR）配体的酶，但对其在哺乳动物中的功能知之甚少。在此我们表明，哺乳动物菱形蛋白酶RHBDL4（也称为Rhbdd1）促进几种膜蛋白，包括EGFR配体TGFα，从内质网（ER）到高尔基体的运输，从而通过细胞外微泡触发它们的分泌。我们的数据还表明，RHBDL4依赖性运输控制受G蛋白偶联受体调节，提示这种菱形蛋白酶在包括EGFR信号传导在内的病理状况中发挥作用。我们提出，RHBDL4响应GPCR信号传导而重新组织早期分泌途径中的运输事件。我们的工作将RHBDL4鉴定为一种调节特定膜蛋白货物分泌动力学和丰度的变阻器。
