Mechanism of secretory cargo sorting at the trans-Golgi Network (TGN)
跨高尔基体网络(TGN)的分泌性货物分类机制
基本信息
- 批准号:10623825
- 负责人:
- 金额:$ 32.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:Adrenal GlandsBiochemical ProcessBlood CirculationBreathingCell Culture TechniquesCell surfaceCellsCellular biologyChromograninsClientCytoplasmic GranulesDepositionDestinationsExtracellular MatrixExtracellular Matrix ProteinsFibroblastsGoalsHealthHumanIGF Type 2 ReceptorIn VitroLiquid substanceMalignant NeoplasmsMechanicsMembraneMental disordersModelingModernizationMolecularMuscleNeuroendocrine CellOrganismPathologyPhasePhysical condensationPlayProcessProtein SecretionProteinsResearchRoleSignal TransductionSignaling MoleculeSkinSortingStimulusStressSystemTissuesWorkcarbohydrate metabolismcell typeextracellularmacromoleculemembrane modelnovelprotein distributionreceptorreconstitutionresponsesecretory proteinsegregationtrans-Golgi Network
项目摘要
Project summary
Protein secretion plays a central role in developing and maintaining multicellular organisms. Specialized cell
types in tissues secrete proteins by regulated or constitutive secretion. Regulated secretion occurs in response
to an extracellular stimulus that elicits the release of signaling molecules, while constitutive secretion facilitates
the deposition of extracellular matrix components that provide tissue integrity. Even though these processes
are highly significant for human health, features that determine whether a protein is secreted by
regulated or constrictive secretion remain unknown. A central regulator of intracellular protein distribution
is the trans-Golgi Network (TGN), which sorts and packages secretory proteins into specific vesicular carriers
targeting them to intracellular storage granules (regulated secretion) or the cell surface (constitutive secretion).
The identification of the mannose-6-phosphate receptor (M6P-R) that recognizes M6P tags of lysosomal led to
the idea that specific sorting receptors also sort secretory proteins. However, conserved recognition signals
or cargo receptors remain unknown. How are these molecules recognized and sorted for targeting the
correct destination?
The concept of concentrating macromolecules into biomolecular condensates by liquid-liquid phase separation
(LLPS) has revolutionized modern cell biology. Human cells use this principle to organize biochemical
processes spatially without a membrane. Our recent research raises the novel possibility that the segregation
of secretory proteins in the TGN lumen follows this concept. Our work has shown that purified chromogranins
(CGs) or Cab45 undergo liquid-liquid phase separation (LLPS) in the milieu of TGN. Both proteins have been
suggested to co-aggregate with secreted proteins (clients) to facilitate their sorting and packaging. We show
that CG or Cab45 liquids, not solid aggregates, are essential for client sorting and packaging. Nonetheless,
the underlying mechanisms of LLPS-dependent client packaging remain elusive. Therefore, our long-term
goal is to understand the molecular basis of LLPS-dependent cargo sorting for regulated (by CGs) and
constitutive (by Cab45) secretion.
Our proposal aims at identifying the mechanisms of LLPS-dependent sorting in reconstituted systems that
recreate the milieu of the TGN lumen. We will include model membranes to examine if and how these
condensates associate with the luminal leaflet of the TGN. We will use cell culture models of regulated (P12
cells) or constitutive (skin fibroblasts) secretion to validate our in-vitro results in living cells. Our concept will
establish the molecular requirements for condensate formation, the mechanisms of client recognition and
vesicular formation in regulated and constitutive secretion. These results will provide a fundamental
understanding of an exciting new paradigm in cell biology and impact the research of pathologies
caused by defective protein secretion, such as psychiatric disorders or cancer.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Julia von Blume其他文献
Julia von Blume的其他文献
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{{ truncateString('Julia von Blume', 18)}}的其他基金
Mechanism of secretory cargo export from the TGN
TGN 秘密货物出口机制
- 批准号:
10408694 - 财政年份:2019
- 资助金额:
$ 32.79万 - 项目类别:
Mechanism of secretory cargo export from the TGN
TGN 秘密货物出口机制
- 批准号:
10389640 - 财政年份:2019
- 资助金额:
$ 32.79万 - 项目类别:
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