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PIK3IP1/TrIP 通过抑制 PI3K/Akt 来限制 T 细胞的激活。

PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt.

机构信息

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Interdisciplinary Biomedical Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA.

出版信息

J Exp Med. 2018 Dec 3;215(12):3165-3179. doi: 10.1084/jem.20172018. Epub 2018 Nov 14.

DOI:10.1084/jem.20172018
PMID:30429249
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6279406/
Abstract

Phosphatidylinositol-3 kinases (PI3Ks) modulate cellular growth, proliferation, and survival; dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or transmembrane inhibitor of PI3K [TrIP]) is a putative transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular domain with homology to the inter-SH2 domain of the PI3K regulatory subunit p85, but the mechanism of TrIP function is poorly understood. We show that both the kringle and p85-like domains are necessary for TrIP inhibition of PI3K and that TrIP is down-modulated from the surface of T cells during T cell activation. In addition, we present evidence that the kringle domain may modulate TrIP function by mediating oligomerization. Using an inducible knockout mouse model, we show that TrIP-deficient T cells exhibit more robust activation and can mediate clearance of infection faster than WT mice. Thus, TrIP is a negative regulator of T cell activation and may represent a novel target for immune modulation.

摘要

磷脂酰肌醇-3 激酶 (PI3Ks) 调节细胞生长、增殖和存活；PI3K 途径的失调可导致自身免疫性疾病和癌症。PIK3IP1（或 PI3K 的跨膜抑制剂 [TrIP]）是 PI3K 的假定跨膜调节剂。TrIP 包含一个细胞外kringle 结构域和一个与 PI3K 调节亚基 p85 的 SH2 结构域内同源的细胞内结构域，但 TrIP 的功能机制知之甚少。我们表明，kringle 和 p85 样结构域对于 TrIP 抑制 PI3K 都是必需的，并且在 T 细胞激活过程中，TrIP 从 T 细胞表面下调。此外，我们提供的证据表明，kringle 结构域可能通过介导寡聚化来调节 TrIP 的功能。使用可诱导的敲除小鼠模型，我们表明 TrIP 缺陷的 T 细胞表现出更强的激活作用，并能比 WT 小鼠更快地清除感染。因此，TrIP 是 T 细胞激活的负调节剂，可能代表免疫调节的一个新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/e76ceef4b366/JEM_20172018_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/af653bb6e72e/JEM_20172018_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/56dfb4af74ab/JEM_20172018_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/4489924b17b5/JEM_20172018_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/d5dcc4ba9eff/JEM_20172018_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/2a09efa77b49/JEM_20172018_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/56f6f23546aa/JEM_20172018_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/c0734674dd12/JEM_20172018_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/80bfa219d976/JEM_20172018_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/f49381ec94c5/JEM_20172018_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/e76ceef4b366/JEM_20172018_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/af653bb6e72e/JEM_20172018_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/56dfb4af74ab/JEM_20172018_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/4489924b17b5/JEM_20172018_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/d5dcc4ba9eff/JEM_20172018_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/2a09efa77b49/JEM_20172018_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/56f6f23546aa/JEM_20172018_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/c0734674dd12/JEM_20172018_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/80bfa219d976/JEM_20172018_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/f49381ec94c5/JEM_20172018_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/655c/6279406/e76ceef4b366/JEM_20172018_Fig9.jpg

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