Elucidating the pathways and machinery of constitutive secretion

阐明组成性分泌的途径和机制

• 批准号: BB/L002841/1
• 负责人: Andrew Peden
• 金额: $ 44.08万
• 依托单位: University of Sheffield
• 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=BB%2FL002841%2F1
• 关键词: Elucidating; pathways; machinery; constitutive; secretion

The human body is made up from billions of cells and each of these cells is further organised into a series of compartments. Cells in some ways resemble miniature cities and these compartments are just like factories that make specific products, for example the endoplasmic reticulum is involved in making proteins and lipids. Once a protein or lipid has been made, its function is often required somewhere else within the cell. To transport these proteins and lipids to the site where they are needed, small packages (vesicles) break off from one compartment and fuse with another, thereby delivering their contents. These vesicles are just like lorries taking goods to different destinations within the city. In some cases the newly made proteins are required outside the cell so the vesicles carrying these proteins fuse with the membrane that covers the cell surface (plasma membrane). This process is called constitutive secretion and is required for many important processes such as inflammation and immune system function. Changes in secretion can cause disease and there is an increasing number of rare genetic disorders cause by mutations in proteins required for secretion. My laboratory is interested in identifying and characterising proteins required for generating, transporting and fusing secretory vesicles with the plasma membrane. To identify this machinery we have developed new ways of measuring secretion and used them with technologies that allow the function of individual genes to be disrupted. Using this approach we have identified two proteins, STX19 and SNAP29, that are required for secretion. This proposal aims to characterise the function of these proteins, in particular we are interested in understanding how SNAP29 and STX19 are regulated and how these proteins are targeted to the correct place within the cell. We are also interested in determining whether SNAP29 and STX19 are involved in the secretion of all types of proteins from cells or just a specific subset.This work will benefit society because it will increase our understanding of a fundamental cellular process and in the future may help in the development of new diagnostics or therapeutics for the treatment of diseases caused by defective secretion. In particular, our work should help in understanding the pathologies which occur in the rare fatal disease CEDNIK (CErebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma) syndrome which is caused by the loss of SNAP29.

人体由数十亿个细胞组成，每个细胞又被进一步组织成一系列的隔间。细胞在某些方面类似于微型城市，这些隔间就像制造特定产品的工厂，例如，内质网参与制造蛋白质和脂类。一旦蛋白质或脂肪形成，它的功能通常需要细胞内的其他地方。为了将这些蛋白质和脂类运送到需要它们的地方，小包裹(囊泡)从一个隔室分离并与另一个隔室融合，从而传递它们的内容物。这些泡泡就像卡车将货物运往城市内的不同目的地。在某些情况下，新产生的蛋白质需要在细胞外，因此携带这些蛋白质的小泡与覆盖细胞表面的膜(质膜)融合。这个过程被称为结构性分泌，是炎症和免疫系统功能等许多重要过程所必需的。分泌的变化会导致疾病，越来越多的罕见遗传疾病是由分泌所需的蛋白质突变引起的。我的实验室感兴趣的是识别和表征产生、运输和融合分泌小泡与质膜所需的蛋白质。为了识别这种机制，我们开发了测量分泌物的新方法，并将其与允许单个基因功能被扰乱的技术一起使用。利用这种方法，我们已经鉴定出分泌所需的两种蛋白质，STX19和SNAP29。这项建议旨在描述这些蛋白质的功能，特别是我们有兴趣了解SNAP29和STX19是如何调控的，以及这些蛋白质是如何被靶向细胞内的正确位置的。我们还有兴趣确定SNAP29和STX19是否参与了细胞中所有类型的蛋白质的分泌，还是只参与了一个特定的子集。这项工作将使社会受益，因为它将增加我们对基本细胞过程的理解，并在未来可能有助于开发新的诊断或治疗方法来治疗由分泌缺陷引起的疾病。特别是，我们的工作应该有助于理解由SNAP29缺失引起的罕见致命疾病CEDNIK(脑发育不良、神经病变、鱼鳞病和角皮病)综合征的病理机制。

项目成果

Organelle tethering, pore formation and SNARE compensation in the late endocytic pathway.

• DOI: 10.1242/jcs.255463
• 发表时间: 2021-05-15
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Davis LJ;Bright NA;Edgar JR;Parkinson MDJ;Wartosch L;Mantell J;Peden AA;Luzio JP
• 通讯作者: Luzio JP

VAMP3/Syb and YKT6 are required for the fusion of constitutive secretory carriers with the plasma membrane.

• DOI: 10.1371/journal.pgen.1006698
• 发表时间: 2017-04
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Gordon DE;Chia J;Jayawardena K;Antrobus R;Bard F;Peden AA
• 通讯作者: Peden AA

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.

• DOI: 10.1126/science.abe9403
• 发表时间: 2020-12-04
• 期刊: Science (New York, N.Y.)
• 作者: Gordon DE;Hiatt J;Bouhaddou M;Rezelj VV;Ulferts S;Braberg H;Jureka AS;Obernier K;Guo JZ;Batra J;Kaake RM;Weckstein AR;Owens TW;Gupta M;Pourmal S;Titus EW;Cakir M;Soucheray M;McGregor M;Cakir Z;Jang G;O'Meara MJ;Tummino TA;Zhang Z;Foussard H;Rojc A;Zhou Y;Kuchenov D;Hüttenhain R;Xu J;Eckhardt M;Swaney DL;Fabius JM;Ummadi M;Tutuncuoglu B;Rathore U;Modak M;Haas P;Haas KM;Naing ZZC;Pulido EH;Shi Y;Barrio-Hernandez I;Memon D;Petsalaki E;Dunham A;Marrero MC;Burke D;Koh C;Vallet T;Silvas JA;Azumaya CM;Billesbølle C;Brilot AF;Campbell MG;Diallo A;Dickinson MS;Diwanji D;Herrera N;Hoppe N;Kratochvil HT;Liu Y;Merz GE;Moritz M;Nguyen HC;Nowotny C;Puchades C;Rizo AN;Schulze-Gahmen U;Smith AM;Sun M;Young ID;Zhao J;Asarnow D;Biel J;Bowen A;Braxton JR;Chen J;Chio CM;Chio US;Deshpande I;Doan L;Faust B;Flores S;Jin M;Kim K;Lam VL;Li F;Li J;Li YL;Li Y;Liu X;Lo M;Lopez KE;Melo AA;Moss FR 3rd;Nguyen P;Paulino J;Pawar KI;Peters JK;Pospiech TH Jr;Safari M;Sangwan S;Schaefer K;Thomas PV;Thwin AC;Trenker R;Tse E;Tsui TKM;Wang F;Whitis N;Yu Z;Zhang K;Zhang Y;Zhou F;Saltzberg D;QCRG Structural Biology Consortium;Hodder AJ;Shun-Shion AS;Williams DM;White KM;Rosales R;Kehrer T;Miorin L;Moreno E;Patel AH;Rihn S;Khalid MM;Vallejo-Gracia A;Fozouni P;Simoneau CR;Roth TL;Wu D;Karim MA;Ghoussaini M;Dunham I;Berardi F;Weigang S;Chazal M;Park J;Logue J;McGrath M;Weston S;Haupt R;Hastie CJ;Elliott M;Brown F;Burness KA;Reid E;Dorward M;Johnson C;Wilkinson SG;Geyer A;Giesel DM;Baillie C;Raggett S;Leech H;Toth R;Goodman N;Keough KC;Lind AL;Zoonomia Consortium;Klesh RJ;Hemphill KR;Carlson-Stevermer J;Oki J;Holden K;Maures T;Pollard KS;Sali A;Agard DA;Cheng Y;Fraser JS;Frost A;Jura N;Kortemme T;Manglik A;Southworth DR;Stroud RM;Alessi DR;Davies P;Frieman MB;Ideker T;Abate C;Jouvenet N;Kochs G;Shoichet B;Ott M;Palmarini M;Shokat KM;García-Sastre A;Rassen JA;Grosse R;Rosenberg OS;Verba KA;Basler CF;Vignuzzi M;Peden AA;Beltrao P;Krogan NJ
• 通讯作者: Krogan NJ

Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages.

• DOI: 10.1111/cmi.12485
• 发表时间: 2016-01
• 期刊: Cellular microbiology
• 影响因子: 3.4
• 作者: Jubrail J;Morris P;Bewley MA;Stoneham S;Johnston SA;Foster SJ;Peden AA;Read RC;Marriott HM;Dockrell DH
• 通讯作者: Dockrell DH