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.

项目概要/摘要 T 细胞受体 (TCR) 的参与启动了一系列复杂的刺激和调节级联反应我们拥有高度精确控制 T 细胞增殖、存活和分化的信号。最近将TCR诱导自噬（TCR-IA）定义为调节TCR信号的新机制通过高度选择性降解关键信号分子进行转导我们已经证明 TCR-IA 是独立于 Vps34，III 类磷酸肌醇 3 激酶 (PI3K) 参与大多数自噬途径。我们的初步数据表明 TCR-IA 依赖于 I 类 PI3K 和肌醇磷酸酶，包括 SHIP1/2 和 Inpp4A/B 在 TCR-IA 末端步骤的研究中，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将其命名为“POLKADOTS 信号体”，其中多功能接头分子 p62 发挥着重要作用我们最近的数据表明，信号转导接头 Bcl10 是针对 TCR-IA 降解的。我们还发现细胞周期蛋白依赖性激酶的降解。抑制剂 p27 需要 p62 表达，这表明 p62 是分子机器（分子机器）的重要组成部分。 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选择性降解TCR-IA靶标，并确定其后果破坏该途径中 T 细胞效应器分化和功能的最终步骤我们将实现这些目标。通过三个目标实现目标目标 1 的目标是定义 TCR 所依赖的细胞质信号传导途径。信号传导导致自噬体从头产生，特别强调 SHIP1/2 和 Inpp4A/B。我们在目标 2 中的研究将确定 p62 和 POLKADOTS 的分子机制。信号体伙伴指导 TCR 诱导的靶分子选择性自噬。诱导性 p62 敲除模型，用于确定 p62 和 p62 依赖性 TCR-IA 在体内生成中的作用我们期望这些数据能够共同定义 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。可能最终会产生新颖且高度特异性的体内 T 细胞反应操纵策略，可能适用于多种人类疾病，如自身免疫、移植排斥和癌症。

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

Longitudinal Tracing of Lyssavirus Infection in Mice via In Vivo Bioluminescence Imaging.

通过体内生物发光成像纵向追踪小鼠狂犬病病毒感染。

DOI：
10.1007/978-1-0716-2453-1_30
发表时间：
2022
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Mastraccio,KateE;Huaman,Celeste;Laing,EricD;Broder,ChristopherC;Schaefer,BrianC
通讯作者：
Schaefer,BrianC