Abstract：
The primary cilium, hereafter cilium, is an antenna-like organelle that modulates intracellular responses, including autophagy, a lysosomal degradation process essential for cell homeostasis. Dysfunction of the cilium is associated with impairment of autophagy and diseases known as \"ciliopathies\". The discovery of autophagy-related proteins at the base of the cilium suggests its potential role in coordinating autophagy initiation in response to physiopathological stimuli. One of these proteins, beclin-1 (BECN1), it which is necessary for autophagosome biogenesis. Additionally, polycystin-2 (PKD2), a calcium channel enriched at the cilium, is required and sufficient to induce autophagy in renal and cancer cells. We previously demonstrated that PKD2 and BECN1 form a protein complex at the endoplasmic reticulum in non-ciliated cells, where it initiates autophagy, but whether this protein complex is present at the cilium remains unknown. Anorexigenic pro-opiomelanocortin (POMC) neurons are ciliated cells that require autophagy to maintain intracellular homeostasis. POMC neurons are sensitive to metabolic changes, modulating signaling pathways crucial for controlling food intake. Exposure to the saturated fatty acid palmitic acid (PA) reduces ciliogenesis and inhibits autophagy in these cells. Here, we show that PKD2 and BECN1 form a protein complex in N43/5 cells, an in vitro model of POMC neurons, and that both PKD2 and BECN1 locate at the cilium. In addition, our data show that the cilium is required for PKD2-BECN1 protein complex formation and that PA disrupts the PKD2-BECN1 complex, suppressing autophagy. Our findings provide new insights into the mechanisms by which the cilium controls autophagy in hypothalamic neuronal cells.
摘要：
初级纤毛,此后纤毛，是调节细胞内反应的天线状细胞器，包括自噬,细胞稳态所必需的溶酶体降解过程。纤毛功能障碍与自噬受损和称为“纤毛病”的疾病有关。在纤毛底部的自噬相关蛋白的发现表明其在响应生理病理刺激协调自噬启动中的潜在作用。这些蛋白质中的一种，Beclin-1(BECN1),它是自噬体生物发生所必需的。此外,多囊藻毒素-2（PKD2），纤毛处富含钙通道，是必需的，并且足以在肾和癌细胞中诱导自噬。我们先前证明PKD2和BECN1在非纤毛细胞的内质网形成蛋白质复合物，它启动自噬，但是这种蛋白质复合物是否存在于纤毛仍然未知。致阳极前黑皮素（POMC）神经元是纤毛细胞，需要自噬来维持细胞内稳态。POMC神经元对代谢变化敏感，调节信号通路对控制食物摄入至关重要。暴露于饱和脂肪酸棕榈酸（PA）减少纤毛生成并抑制这些细胞中的自噬。这里,我们显示PKD2和BECN1在N43/5细胞中形成蛋白质复合物，POMC神经元的体外模型，PKD2和BECN1都位于纤毛。此外,我们的数据表明，纤毛是PKD2-BECN1蛋白复合物形成所必需的，PA破坏PKD2-BECN1复合物，抑制自噬。我们的发现为纤毛控制下丘脑神经元细胞自噬的机制提供了新的见解。
