Litaf, a novel driver of membrane protrusion pathways

组织内细胞的行为受其对环境的反应控制。细胞表面的受体分子接受大量的化学和物理刺激，将信号传递到细胞内部，控制细胞迁移、代谢、细胞增殖和分化等重要过程。这些信号传输的异常会导致癌症、糖尿病、肌肉萎缩症和神经退化等疾病的病理状态。细胞接收到的最重要的信号之一是来自循环中的小蛋白质——生长因子。它们与专门的受体结合，作为对生长因子参与的反应，这些受体改变了它们与细胞内许多分子相互作用的模式，从而产生所谓的“有丝分裂反应”。这种反应包括细胞行为的许多变化（如生长、分裂和迁移）。生长因子受体研究得最好的例子之一是表皮生长因子受体（EGFR），它控制着细胞生长的许多方面。EGFR的表达增加与几种类型的癌症有关。为了防止过度刺激细胞对生长因子的反应，有一些调节机制来确保这些反应不会无休止地持续下去，从而导致细胞分裂和增殖失控。这些机制包括受体在受到刺激时的内化，将其从细胞表面引导到细胞内特殊的膜封闭腔室（称为内体）。受体从核内体进入另一个被称为溶酶体的膜封闭腔室，在那里它们最终被破坏。通往核内体的途径称为内吞途径。我们发现了控制EGFR摄取及其通过内吞途径运动的细胞途径的关键要素。这些元素识别受刺激的受体，并重新塑造其周围的局部膜，以便受体可以从细胞表面移动到核内体，然后再移动到溶酶体。目前的应用涉及我们发现的一种新的蛋白质元素，称为LITAF。我们的初步数据表明，LITAF可以改变膜的形状，从而通过内吞途径帮助EGFR的运输。内吞途径在防止病毒和细菌感染以及消除积聚在细胞内并导致阿尔茨海默病、帕金森病和亨廷顿病中观察到的神经变性的蛋白质聚集体方面也至关重要。事实上，LITAF（脂多糖诱导的TNF因子）最初被确定为细胞在暴露于细菌毒素时大量产生的一种蛋白质。LITAF的功能可能在某种程度上与帮助产生免疫反应的内吞途径的功能有关，尽管我们还不知道这种联系是什么。此外，在人群中发生的LITAF突变会导致一种称为Charcot Marie Tooth病的衰弱性瘫痪，这是由周围神经系统髓鞘的丢失引起的。我们希望我们从这个项目中获得的信息将有助于我们了解髓鞘的健康是如何正常维持的。总之，我们的调查所获得的知识将为许多由控制内吞途径的蛋白质突变引起的疾病的分子基础带来新的见解，并从长远来看将指导进一步的药理干预工作。

The behaviour of cells within a tissue is controlled by their response to the environment. Receptor molecules at the cell surface receive a large number of chemical and physical stimuli that transmit signals to the interior of the cell and control important processes such cell migration, metabolism, cell proliferation and differentiation. Anomalies in the transmission of such signals result in pathological states that derive in diseases like cancer, diabetes, muscular dystrophy and neurological degeneration. Amongst the most important signals that cells receive are from circulating small proteins called growth factors. These bind to specialised receptors, that in response to growth factor engagement alter their pattern of interactions with many molecules inside the cell to generate a so-called 'mitogenic response'. This response encompasses many changes to the cell's behaviour (such as growth, division and migration). One of the best-studied examples of a growth factor receptor is the epidermal growth factor receptor (EGFR), which controls many aspects of cell growth. Increased expression of EGFR is linked to several types of cancer. In order to prevent overstimulation of the cell response to growth factors, there are mechanisms of regulation to ensure that these responses are not sustained endlessly, which would lead to uncontrolled cell division and proliferation. These mechanisms encompass the internalisation of the receptor upon stimulation, leading it from the cell surface to specialised membrane-enclosed compartments within the cell (called endosomes). From endosomes, receptors pass to another membrane-enclosed compartment called the lysosome, where they are ultimately destroyed. The pathway to the endosome is termed the endocytic pathway. We discovered key elements of the cellular pathway that controls the uptake of EGFR and its movement through the endocytic pathway. These elements recognise the stimulated receptor and re-shape the local membrane around it so that the receptor can move from the cell surface to endosomes and then to lysosomes. The current application concerns a new protein element that we have discovered, called LITAF. Our preliminary data suggest that LITAF can alter the shape of membranes and thus aid the transport of EGFR through the endocytic pathway.The endocytic pathway is also critical in protecting against viral and bacterial infections and to eliminate protein aggregates that otherwise accumulate inside cells and result in the neurodegeneration observed in Alzheimer's, Parkinson's and Huntington's diseases. In fact, LITAF (lipopolysaccharide-induced TNF factor) was first identified as a protein that the cell produces in high quantity as a response to exposure to bacterial toxins. It is likely that the function of LITAF is linked in some way to the function of the endocytic pathway in helping to generate immune responses, though we do not yet know what the link is. In addition, mutations within LITAF that occur in the population lead to a debilitating paralysis termed Charcot Marie Tooth disease, caused by loss of myelin sheaths from the peripheral nervous system. We hope that information we gain from this project will help us understand how the health of the myelin sheath is normally maintainedIn summary, the knowledge gained by our investigations will bring new insights into the molecular basis of many diseases caused by mutations in proteins that control the endocytic pathway, and in the long-term will guide further efforts for pharmacological intervention.