Role of Integrins in Natural Killer Cell Function

整合素在自然杀伤细胞功能中的作用

• 批准号: 9566718
• 负责人: Eric O Long
• 金额: $ 17.77万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9566718
• 关键词: Adhesions; Antigen-Presenting Cells; Biochemical; Bioinformatics; CD18 Antigens; Cell Degranulation; Cell physiology; Cells; Cytoplasmic Granules; Family; Family member; Goals; Guanine; Guanine Nucleotide Exchange Factors; Inflammatory Response; Integrin Binding; Integrins; Ligand Binding; Lytic; Mass Spectrum Analysis; Microtubule-Organizing Center; Monomeric GTP-Binding Proteins; NK Cell Activation; Natural Killer Cells; Orphan; PH Domain; Play; Proteins; Role; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Time; Virus; cell killing; chemokine; cytohesin-1; cytokine; intercellular cell adhesion molecule; killings; member; neoplastic cell; receptor; receptor binding; response

In NK cells, beta2 integrin binding to ICAM family members is sufficient to promote not only adhesion to target cells, but also the polarization of intracellular lytic granules towards the target. Using unbiased mass spectrometry and bioinformatics analysis of NK cells that had been stimulated through beta2 integrin LFA-1 resulted in the discovery of a complete signaling pathway that controls granule polarization toward the target cell. In addition to a network of 11 proteins tested for a role in granule polarization, there were 12 orphan proteins with no known interactions. The orphan protein with the highest score in the mass spectrometry analysis was cytohesin 4. The four members of the cytohesin family carry a PH domain and a Sec7 domain with guanine exchange factor activity for members of the small GTPase Arf family. While cytohesin 1 plays a role in inside-out signaling for beta2 integrin LFA-1, the function of cytohesin 4 is unknown. Silencing of cytohesin 4 but not cytohesin 1 resulted in defective granule polarization. To our knowledge, this is the first time a function has been attributed to cytohesin 4.

在NK细胞中，与ICAM家族成员结合的β2整合素不仅足以促进靶细胞的粘附，而且还足以促进细胞内裂解颗粒对靶标的粘附。使用通过beta2整合素LFA-1刺激的NK细胞的无偏质谱和生物信息学分析，从而发现了一个完整的信号传导途径，该途径控制颗粒朝向目标细胞。除了在颗粒极化中测试了11种蛋白质的网络外，还有12个孤儿蛋白，没有已知相互作用。在质谱分析中得分最高的孤儿蛋白是细胞粘着蛋白4。细胞粘着蛋白家族的四个成员携带一个pH结构域和一个SEC7结构域，为小GTPase ARF家族的成员带有鸟嘌呤交换因子活性。虽然细胞粘着蛋白1在Beta2整合素LFA-1的内而外信号传导中起作用，但细胞粘着蛋白4的功能尚不清楚。细胞粘着蛋白4但没有细胞粘着素1的沉默导致颗粒极化。据我们所知，这是函数首次归因于细胞粘着素4。

项目成果

A signaling network stimulated by β2 integrin promotes the polarization of lytic granules in cytotoxic cells.

• DOI: 10.1126/scisignal.2005629
• 发表时间: 2014-10-07
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Zhang M;March ME;Lane WS;Long EO
• 通讯作者: Long EO

ICAM-1: getting a grip on leukocyte adhesion.

• DOI: 10.4049/jimmunol.1100646
• 发表时间: 2011-05-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Long EO

Integrin-dependent organization and bidirectional vesicular traffic at cytotoxic immune synapses.

• DOI: 10.1016/j.immuni.2009.05.009
• 发表时间: 2009-07-17
• 期刊: IMMUNITY
• 影响因子: 32.4
• 作者: Liu, Dongfang;Bryceson, Yenan T.;Meckel, Tobias;Vasiliver-Shamis, Gaia;Dustin, Michael L.;Long, Eric O.
• 通讯作者: Long, Eric O.

Tethering of intercellular adhesion molecule on target cells is required for LFA-1-dependent NK cell adhesion and granule polarization.

• DOI: 10.4049/jimmunol.1000761
• 发表时间: 2010-09-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Gross CC;Brzostowski JA;Liu D;Long EO
• 通讯作者: Long EO