未成熟 CD4+ T 细胞向 T 辅助 2 细胞（Th2 细胞）的分化
中文名称
通路描述
未成熟（未接触抗原）的 CD4+ T 细胞通过与呈递抗原肽的树突状细胞（DC）接触，在 MHC II 复合物的辅助下被诱导分化为 T 辅助 2 细胞（Th2 细胞）。抗原肽通过 T 细胞受体（TCR）激活信号，该信号通过与树突状细胞上的 CD80 或 CD86 与 T 细胞上的 CD28 之间的相互作用而被放大。树突状细胞还分泌细胞因子，决定 CD4+ T 细胞分化为各种辅助和调节亚群的过程称为极化。树突状细胞分泌的启动 Th2 分化的特定细胞因子尚不明确，可能是白细胞介素 -2（IL2）。来自树突状细胞或 T 细胞的 IL2 激活 T 细胞内的信号，产生磷酸化的 STAT5 二聚体。STAT5 二聚体结合并激活编码 IL4R 的基因（Liao 等，2008），这是 IL4 受体的亚基，导致 IL4 位点的染色质开放（Cote-Sierra 等，2004）。IL4 信号在 CD4+ T 细胞中产生磷酸化的 STAT6 二聚体，它们结合编码 GATA3 的基因（Onodera 等，2010，综述 Onodera 等，2018），GATA3 是 Th2 分化的主要调节因子。STAT6 二聚体还结合 RAD50 基因 3'区的启动子控制区（LCR）（Lee 和 Rao 2004），该基因位于包含编码 Th2 细胞因子 IL4、IL5 和 IL13 的基因簇中，并促进其表达（Lee 等，2003）。GATA3 的表达也受 NFATC2（NFAT1）和 NICD1、NICD2 的激活，分别来自 TCR 信号（Scheiman 和 Avri 等，2009）和 Notch 信号（Amsen 等，2004, 2007, Fang 等，2007，综述 Nakayama 和 Yamashita 2008, Zhu 等，2010）。GATA3 足以引导 Th2 分化，包括 Th2 特征性细胞因子的表达（Ouyang 等，2000）。GATA3（Kanhere 等，2012）、STAT6 二聚体（Lee 和 Rao 2004）和其他因子结合 LCR，招募染色质修饰因子，通过乙酰化组蛋白打开该区域（Wurster 和 Pazin 2008）。Th2 细胞通过表达和分泌 IL4、IL5 和 IL13 的细胞因子而具有特征，这些细胞因子由位于人类染色体 5（小鼠中为染色体 11）上的 LCR 簇中的基因编码。GATA3、NFATC2 和其他因子结合 IL4 基因和 IL13 基因的启动子并激活表达。GATA3 结合 IL5 基因，可以激活或抑制其表达，取决于结合位点（Schwenger 等，2001, Zhang 等，1997, Lee 等，1998, Sasaki 等，2013）。
英文描述
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane Tail-anchored (TA) proteins have a hydrophobic transmembrane domain (TMD) located near the C-terminus ("tail") of the protein. Depending on the nature of the TMD, TA proteins can be inserted into the endoplasmic reticulum (ER) membrane by at least 4 mechanisms: cotranslational insertion by the signal recognition particle (SRP), post-translational insertion by ASNA1 (TRC40), post-translational insertion by the SRP, and post-translational insertion by a SRP-independent mechanism (SND) (Casson et al. 2017, reviewed in Borgese and Fasana 2011, Casson et al. 2016, Aviram et al. 2016, Chio et al. 2017). Much of the information about the mammalian system of insertion by ASNA1 (TRC40) has been inferred from the Saccharomyces cerevisiae homologue Get3.
Prior to post-translational insertion by ASNA1, SGTA binds the transmembrane domain of the substrate TA protein immediately after translation (Leznicki et al. 2011, Leznicki and High 2012, Xu et al. 2012, Wunderly et al. 2014, Shao et al. 2017), the SGTA:TA protein complex then binds the BAG6 complex (BAG6:GET4:UBL4A) via UBL4A (Winnefeld et al. 2006, Chartron et al. 2012, Xu et al. 2012, Leznicki et al. 2013, Mock et al. 2015, Kuwabara et al. 2015, Shao et al. 2017), and the TA protein is transferred to ASNA1 (Mariappan et al. 2010, Leznicki et al. 2011, Shao et al. 2017), also bound by the BAG6 complex via UBL4A. The ASNA1:TA protein complex then docks at the WRB:CAMLG (WRB:CAML) complex located in the ER membrane and the TA protein is inserted into the ER membrane by an uncharacterized mechanism that involves ATP and the transmembrane domain insertase activity of the WRB:CAML complex (Vilardi et al. 2011, Vilardi et al. 2014, Vogl et al. 2016, and inferred from yeast in Wang et al. 2014).
Misfolded TA proteins, overexpressed TA proteins, and membrane proteins mislocalized in the cytosol bind SGTA but are not efficiently transferred to ASNA1 and, instead, are retained by BAG6 which recruits RNF126 to ubiquitinate them, targeting them for degradation by the proteasome (Wang et al. 2011, Leznicki and High 2012, Xu et al. 2012, Rodrigo-Brenni et al. 2014, Wunderly et al. 2014, Shao et al. 2017, reviewed in Lee and Ye 2013, Casson et al. 2016, Krysztofinska et al. 2016, Guna and Hegde 2018).
Prior to post-translational insertion by ASNA1, SGTA binds the transmembrane domain of the substrate TA protein immediately after translation (Leznicki et al. 2011, Leznicki and High 2012, Xu et al. 2012, Wunderly et al. 2014, Shao et al. 2017), the SGTA:TA protein complex then binds the BAG6 complex (BAG6:GET4:UBL4A) via UBL4A (Winnefeld et al. 2006, Chartron et al. 2012, Xu et al. 2012, Leznicki et al. 2013, Mock et al. 2015, Kuwabara et al. 2015, Shao et al. 2017), and the TA protein is transferred to ASNA1 (Mariappan et al. 2010, Leznicki et al. 2011, Shao et al. 2017), also bound by the BAG6 complex via UBL4A. The ASNA1:TA protein complex then docks at the WRB:CAMLG (WRB:CAML) complex located in the ER membrane and the TA protein is inserted into the ER membrane by an uncharacterized mechanism that involves ATP and the transmembrane domain insertase activity of the WRB:CAML complex (Vilardi et al. 2011, Vilardi et al. 2014, Vogl et al. 2016, and inferred from yeast in Wang et al. 2014).
Misfolded TA proteins, overexpressed TA proteins, and membrane proteins mislocalized in the cytosol bind SGTA but are not efficiently transferred to ASNA1 and, instead, are retained by BAG6 which recruits RNF126 to ubiquitinate them, targeting them for degradation by the proteasome (Wang et al. 2011, Leznicki and High 2012, Xu et al. 2012, Rodrigo-Brenni et al. 2014, Wunderly et al. 2014, Shao et al. 2017, reviewed in Lee and Ye 2013, Casson et al. 2016, Krysztofinska et al. 2016, Guna and Hegde 2018).
所含基因
19 个基因