T cell receptor-activated autophagy as a regulator of T cell effector responses

T 细胞受体激活的自噬作为 T 细胞效应反应的调节剂

基本信息

批准号：
10170215
负责人：
THOMAS Patrick CONRADS
金额：
$ 61.3万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-16 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170215
关键词：
Adoptive Transfer Anabolism Antigens Autoimmunity Autophagocytosis Autophagosome Biochemical Biochemistry CD69 antigen Collaborations Complex Data Degradation Pathway Drug Targeting Exhibits Gene Silencing Gene Targeting Generations Genes Goals Graft Rejection Image Immune response Impairment Infection Inositol Knock-out Lead Ligation Listeriosis Malignant Neoplasms Mass Spectrum Analysis Mediator of activation protein Memory Methodology Microscopy Modeling Molecular Molecular Machines Names Pathway interactions Pharmaceutical Preparations Pharmacology Phosphoric Monoester Hydrolases Phosphotransferases Play Polyphosphates Production Proteins Proteolysis Proteomics Receptor Signaling Regulatory Pathway Resolution Role Shigella Infections Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA T cell differentiation T cell response T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte Therapeutic Work cell type conditional knockout cyclin-dependent kinase inhibitor 1B effector T cell human disease in vivo inositol-1,4,5-trisphosphate 5-phosphatase mutant novel novel strategies novel therapeutic intervention novel therapeutics pathogen recruit response src Homology Region 2 Domain

项目摘要

Project Summary/Abstract Engagement of the T cell receptor (TCR) initiates a complex cascade of stimulatory and regulatory signals that orchestrate highly precise control of T cell proliferation, survival and differentiation. We have recently defined TCR-induced autophagy (TCR-IA) as a novel mechanism that regulates TCR signal transduction via highly selective degradation of key signaling molecules. We have shown that TCR-IA is independent of Vps34, the class III phosphoinositol-3-kinase (PI3K) implicated in most autophagy pathways. Our preliminary data suggest that TCR-IA is dependent on class I PI3K and inositol phosphatases, including SHIP1/2 and Inpp4A/B. In studies of the terminal steps in TCR-IA, we have demonstrated that the selective targeting of T cell signaling intermediates to autophagosomes requires a cytoplasmic signaling complex we have named the “POLKADOTS signalosome,” in which the multi-functional adaptor molecule p62 plays a central role. Our recent data show that the signaling adaptor, Bcl10, is targeted to the TCR-IA degradative pathway via interaction with p62. We have also shown that degradation of the cyclin dependent kinase inhibitor, p27, requires p62 expression, suggesting that p62 is a crucial component of a molecular machine (the POLKADOTS signalosome) that directs TCR-IA-dependent proteolysis of specific targets. The purpose of our proposed studies is to elucidate the molecular mechanisms that connect antigenic stimulation of the TCR to selective degradation of targets of TCR-IA, and to determine the consequences of disruption of terminal steps in this pathway on T cell effector differentiation and function. We will achieve these goals through three Aims. The goal of Aim 1 is to define the cytoplasmic signaling pathway by which TCR signaling leads to de novo production of autophagosomes, with a particular emphasis on SHIP1/2 and Inpp4A/B. Our studies in Aim 2 will determine the molecular mechanism by which p62 and POLKADOTS signalosome partners direct TCR-induced selective autophagy of target molecules. In Aim 3, we will use an inducible p62 knockout model to determine the role of p62 and p62-dependent TCR-IA in generation of in vivo T cell effector responses. Together, we expect these data to define key molecular mechanisms in the TCR-IA pathway, and to define how TCR-IA impacts T cell differentiation for control of pathogen infections. This work may ultimately lead to novel and highly specific strategies for manipulation of in vivo T cell responses, which may be applicable to diverse human diseases such as autoimmunity, transplant rejection, and cancer.

项目摘要/摘要 T细胞受体（TCR）的参与启动了复杂的刺激性和调节性级联信号可以安排对T细胞增殖，生存和分化的高度精确控制的信号。我们有最近定义的TCR诱导的自噬（TCR-IA）是调节TCR信号的新机制通过高度选择性降解的关键信号分子的转导。我们已经表明TCR-ia是独立于VPS34，在大多数自噬途径中实现的III类磷酸肌醇-3-激酶（PI3K）。我们的初步数据表明，TCR-IA取决于I类PI3K和肌醇磷酸酶，包括 Ship1/2和Inpp4a/b。在对TCR-IA的终端步骤的研究中，我们证明了选择性将T细胞信号传导中间体靶向自噬体需要细胞质信号传导复合物命名了“ polkadots信号体”，其中多功能适配器分子p62播放A 中心角色。我们最近的数据表明，信号适配器BCl10针对TCR-IA降解性通过与p62相互作用的途径。我们还表明，细胞周期蛋白依赖性激酶的降解抑制剂p27需要p62表达，表明p62是分子机器的关键成分（ Polkadots信号体）指导特定靶标的TCR-IA依赖性蛋白水解。我们提出的研究的目的是阐明连接抗原的分子机制刺激TCR以选择性降解TCR-IA的靶标，并确定在T细胞效应子分化和功能上，该途径中终端步骤的破坏。我们将实现这些通过三个目标进行目标。目标1的目的是定义TCR的细胞质信号通路信号导致从头产生自噬体，特别强调Ship1/2和 inpp4a/b。我们在AIM 2中的研究将确定p62和polkadot的分子机制信号体伴侣直接直接TCR诱导的靶分子选择性自噬。在AIM 3中，我们将使用诱导p62敲除模型，以确定p62和p62依赖性TCR-IA在体内生成中的作用 T细胞效应子响应。我们期望这些数据将定义TCR-IA中的关键分子机制途径，并定义TCR-IA如何影响T细胞分化以控制病原体感染。这项工作最终可能导致新颖且高度具体的策略来操纵体内T细胞反应，这可能适用于自身免疫，移植排斥和癌症等潜水性人类疾病。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CARD19 Interacts with Mitochondrial Contact Site and Cristae Organizing System Constituent Proteins and Regulates Cristae Morphology.

DOI：
10.3390/cells11071175
发表时间：
2022-03-31
期刊：
Cells
影响因子：
6
作者：
Rios KE;Zhou M;Lott NM;Beauregard CR;McDaniel DP;Conrads TP;Schaefer BC
通讯作者：
Schaefer BC

Bcl10 is associated with actin dynamics at the T cell immune synapse.

DOI：
10.1016/j.cellimm.2020.104161
发表时间：
2020-10
期刊：
Cellular immunology
影响因子：
4.3
作者：
Wagh K;Wheatley BA;Traver MK;Hussain I;Schaefer BC;Upadhyaya A
通讯作者：
Upadhyaya A

mAb therapy controls CNS-resident lyssavirus infection via a CD4 T cell-dependent mechanism.

DOI：
10.15252/emmm.202216394
发表时间：
2023-10-11
期刊：
EMBO MOLECULAR MEDICINE
影响因子：
11.1
作者：
Mastraccio, Kate E.;Huaman, Celeste;Coggins, Si'Ana A.;Clouse, Caitlyn;Rader, Madeline;Yan, Lianying;Mandal, Pratyusha;Hussain, Imran;Ahmed, Anwar E.;Ho, Trung;Feasley, Austin;Vu, Bang K.;Smith, Ina L.;Markotter, Wanda;Weir, Dawn L.;Laing, Eric D.;Broder, Christopher C.;Schaefer, Brian C.
通讯作者：
Schaefer, Brian C.

CARD19, the protein formerly known as BinCARD, is a mitochondrial protein that does not regulate Bcl10-dependent NF-κB activation after TCR engagement.

CARD19（以前称为 BinCARD）是一种线粒体蛋白，在 TCR 参与后不调节 Bcl10 依赖性 NF-κB 激活。

DOI：
10.1016/j.cellimm.2020.104179
发表时间：
2020
期刊：
Cellular immunology
影响因子：
4.3
作者：
Rios,KarianaE;Kashyap,AnujK;Maynard,SeanK;Washington,Michael;Paul,Suman;Schaefer,BrianC
通讯作者：
Schaefer,BrianC

Establishment of a longitudinal pre-clinical model of lyssavirus infection.

DOI：
10.1016/j.jviromet.2020.113882
发表时间：
2020-07
期刊：
Journal of virological methods
影响因子：
3.1
作者：
Mastraccio KE;Huaman C;Warrilow D;Smith GA;Craig SB;Weir DL;Laing ED;Smith IL;Broder CC;Schaefer BC
通讯作者：
Schaefer BC