Analysing the cell biology of SNX10 in endosomal sorting and signaling: implications for osteoclast function in osteopetrosis

分析 SNX10 在内体分选和信号转导中的细胞生物学：对骨石症中破骨细胞功能的影响

• 批准号: MR/L007363/1
• 负责人: Peter Cullen
• 金额: $ 48.59万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL007363%2F1
• 关键词: Analysing; cell; biology; SNX10; endosomal

All human cells are composed of an outer boundary that is defined by a complex mixture of protein and lipids called the plasma membrane. This encircles a fluid filled 3-dimensional space, termed the cytosol, which contains additional membrane-enriched compartments each composed of a unique combination of proteins and lipids. For cells to functional normally, proteins and lipids must be efficiently transported to the correct membrane-enriched compartment within this maze of membranes. Not surprisingly, if such transport is perturbed, so that the wrong proteins and lipids are delivered to the incorrect membrane-enriched compartment, cell function can be adversely affected which in turn leads to the development of various diseases. Establishing the mechanisms through which cells achieve regulated protein and lipid transport is therefore a major challenge in cell biology with direct implication for our understanding of human disease.For over 10 years our laboratory has focused on describing the mechanistic details that control regulated transport of proteins and lipids within a specific aspect of the cell's membranous maze termed the endocytic network. In particular, we have studied a family of ancient, evolutionary conserved proteins, the sorting nexins. Within this family we have extensively analysed the function of retromer complexes, and this is generating new insight into the perturbed function of the endosomal network during cell infection by various pathogens, as well as a variety of diseases including Alzheimer's disease and Parkinson's disease.In the current proposal we seek to utilize our extensive experience of studying sorting nexins to define the function of sorting nexin-10 (SNX10) in the regulation of bone re-modeling. This stems from research showing that mutations in SNX10 are linked with autosomal recessive osteopetrosis, a genetically heterogenous disorder caused by reduced bone resorption by a specific class of cells termed osteoclasts. However, at present we do not understand the basic function of SNX10, and hence have a very limited appreciation of why its mutation leads to this debilitating disease.Our proposed research will address the following questions:1). Is SNX10 required for endosomal sorting of RANK and downstream RANKL signaling?2). Is the cell surface expression of other receptors also regulated by SNX10?3). What are the molecular details of SNX10-mediated endosomal sorting?4). Do the molecular details of SNX10-mediated endosomal sorting generate further insight into diseases of bone homeostasis?Overall, data derived from the proposed research, which will be disseminated through peer-review publications and oral presentation at international meetings, will define the role of SNX10 in osteoclast function, knowledge that will achieve a greater appreciation of the cellular defects that lead to osteopetrosis and possibly other related bone diseases. Longer term, the research may provide a rationale for therapeutic intervention in patients carrying the SNX10 mutations and other osteopetrosis-linked mutations.

所有人类细胞都由一个外部边界组成，该外部边界由称为质膜的蛋白质和脂质的复杂混合物定义。它围绕着一个充满液体的三维空间，称为胞质溶胶，其中包含额外的膜富集隔室，每个隔室均由蛋白质和脂质的独特组合组成。为了使细胞正常发挥功能，蛋白质和脂质必须有效地运输到这个膜迷宫内正确的膜富集区室。毫不奇怪，如果这种运输受到干扰，导致错误的蛋白质和脂质被递送到不正确的膜富集区室，细胞功能可能会受到不利影响，进而导致各种疾病的发生。因此，建立细胞实现蛋白质和脂质转运调节的机制是细胞生物学中的一项重大挑战，对我们对人类疾病的理解有直接影响。十多年来，我们的实验室一直致力于描述控制蛋白质和脂质转运调节的机制细节。细胞膜迷宫的一个特定方面（称为内吞网络）内的脂质。特别是，我们研究了一个古老的、进化保守的蛋白质家族，即分选连接蛋白。在这个家族中，我们广泛分析了逆转录酶复合物的功能，这对细胞感染各种病原体以及包括阿尔茨海默病和帕金森病在内的多种疾病期间内体网络的扰动功能产生了新的见解。目前的建议是，我们寻求利用我们研究分选 nexin 的丰富经验来定义分选 nexin-10 (SNX10) 在骨重塑调节中的功能。这源于研究表明，SNX10 的突变与常染色体隐性骨石症有关，这是一种遗传异质性疾病，由称为破骨细胞的特定细胞类骨吸收减少引起。然而，目前我们还不了解 SNX10 的基本功能，因此对其突变导致这种衰弱性疾病的原因了解非常有限。我们提出的研究将解决以下问题：1)。 RANK 和下游 RANKL 信号传导的内体分选是否需要 SNX10？2)。其他受体的细胞表面表达是否也受 SNX10 调节？3)。 SNX10 介导的内体分选的分子细节是什么？4)。 SNX10 介导的内体分选的分子细节是否可以进一步深入了解骨稳态疾病？总体而言，从拟议研究中获得的数据（将通过同行评审出版物和国际会议上的口头报告进行传播）将定义 SNX10 的作用在破骨细胞功能方面，这些知识将更好地了解导致骨石症和可能的其他相关骨疾病的细胞缺陷。从长远来看，这项研究可能为携带 SNX10 突变和其他骨硬化症相关突变的患者的治疗干预提供依据。

项目成果

Endoplasmic Reticulum-Endosome Contact Sites: Specialized Interfaces for Orchestrating Endosomal Tubule Fission?

• DOI: 10.1021/acs.biochem.8b01176
• 发表时间: 2018-12-11
• 期刊: BIOCHEMISTRY
• 影响因子: 2.9
• 作者: Daly, James L.;Cullen, Peter J.
• 通讯作者: Cullen, Peter J.

Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation.

• DOI: 10.1038/s41467-023-39643-7
• 发表时间: 2023-07-03
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Calcagni, Alessia;Staiano, Leopoldo;Zampelli, Nicolina;Minopoli, Nadia;Herz, Niculin J.;Di Tullio, Giuseppe;Huynh, Tuong;Monfregola, Jlenia;Esposito, Alessandra;Cirillo, Carmine;Bajic, Aleksandar;Zahabiyon, Mahla;Curnock, Rachel;Polishchuk, Elena;Parkitny, Luke;Medina, Diego Luis;Pastore, Nunzia;Cullen, Peter J.;Parenti, Giancarlo;De Matteis, Maria Antonietta;Grumati, Paolo;Ballabio, Andrea
• 通讯作者: Ballabio, Andrea

Multi-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health.

• DOI: 10.1038/s41467-023-38719-8
• 发表时间: 2023-05-29
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Daly, James L.;Danson, Chris M.;Lewis, Philip A.;Zhao, Lu;Riccardo, Sara;Di Filippo, Lucio;Cacchiarelli, Davide;Lee, Daehoon;Cross, Stephen J.;Heesom, Kate J.;Xiong, Wen-Cheng;Ballabio, Andrea;Edgar, James R.;Cullen, Peter J.
• 通讯作者: Cullen, Peter J.

Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome.

• DOI: 10.1016/j.cell.2023.04.003
• 发表时间: 2023-05-11
• 期刊: CELL
• 影响因子: 64.5
• 作者: Healy, Michael D.;McNally, Kerrie E.;Butkovic, Rebeka;Chilton, Molly;Kato, Kohji;Sacharz, Joanna;McConville, Calum;Moody, Edmund R. R.;Shaw, Shrestha;Planelles-Herrero, Vicente J.;Yadav, Sathish K. N.;Ross, Jennifer;Borucu, Ufuk;Palmer, Catherine S.;Chen, Kai-En;Croll, Tristan I.;Hall, Ryan J.;Caruana, Nikeisha J.;Ghai, Rajesh;Nguyen, Thi H. D.;Heesom, Kate J.;Saitoh, Shinji;Berger, Imre;Schaffitzel, Christiane;Williams, Tom A.;Stroud, David A.;Derivery, Emmanuel;Collins, Brett M.;Cullen, Peter J.
• 通讯作者: Cullen, Peter J.

Sorting nexin 5 mediates virus-induced autophagy and immunity.

• DOI: 10.1038/s41586-020-03056-z
• 发表时间: 2021-01
• 期刊: Nature
• 影响因子: 64.8
• 作者: Dong X;Yang Y;Zou Z;Zhao Y;Ci B;Zhong L;Bhave M;Wang L;Kuo YC;Zang X;Zhong R;Aguilera ER;Richardson RB;Simonetti B;Schoggins JW;Pfeiffer JK;Yu L;Zhang X;Xie Y;Schmid SL;Xiao G;Gleeson PA;Ktistakis NT;Cullen PJ;Xavier RJ;Levine B
• 通讯作者: Levine B