Chen Qiuyue, Denard Bray, Lee Ching-En, Han Sungwon, Ye James S, Ye Jin
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
Mol Cell. 2016 Aug 18;63(4):567-578. doi: 10.1016/j.molcel.2016.06.032. Epub 2016 Aug 4.
TM4SF20 (transmembrane 4 L6 family 20) is a polytopic membrane protein that inhibits proteolytic processing of CREB3L1 (cAMP response element-binding protein 3-like 1), a membrane-bound transcription factor that blocks cell division and activates collagen synthesis. Here we report that ceramide stimulates CREB3L1 cleavage by inverting the orientation of TM4SF20 in membranes. In the absence of ceramide, the N terminus of the first transmembrane helix of TM4SF20 is inserted into the endoplasmic reticulum (ER) lumen. This translocation requires TRAM2 (translocating chain-associated membrane protein 2), a membrane protein containing a putative ceramide-interacting domain. In the presence of ceramide, the N terminus of the first transmembrane domain of TM4SF20 is exposed to cytosol. Consequently, the membrane topology of TM4SF20 is inverted, and this form of TM4SF20 stimulates CREB3L1 cleavage. In the presence of ceramide, translocation of TM4SF20 is TRAM2-independent. We designate this mechanism-causing regulated inversion of the membrane topology as "regulated alternative translocation."
TM4SF20（跨膜4 L6家族成员20）是一种多次跨膜蛋白，它可抑制CREB3L1（cAMP反应元件结合蛋白3样蛋白1）的蛋白水解加工，CREB3L1是一种膜结合转录因子，可阻断细胞分裂并激活胶原蛋白合成。在此我们报告，神经酰胺通过使TM4SF20在膜中的方向反转来刺激CREB3L1的切割。在没有神经酰胺的情况下，TM4SF20第一个跨膜螺旋的N端插入内质网（ER）腔。这种转运需要TRAM2（转运链相关膜蛋白2），一种含有假定神经酰胺相互作用结构域的膜蛋白。在有神经酰胺的情况下，TM4SF20第一个跨膜结构域的N端暴露于胞质溶胶。因此，TM4SF20的膜拓扑结构发生反转，这种形式的TM4SF20刺激CREB3L1的切割。在有神经酰胺的情况下，TM4SF20的转运不依赖于TRAM2。我们将这种导致膜拓扑结构受调控反转的机制称为“受调控的交替转运”。
