Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN.
Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN.
J Exp Med. 2020 Feb 3;217(2). doi: 10.1084/jem.20190969.
Thymocyte egress is a critical determinant of T cell homeostasis and adaptive immunity. Despite the roles of G protein-coupled receptors in thymocyte emigration, the downstream signaling mechanism remains poorly defined. Here, we report the discrete roles for the two branches of mevalonate metabolism-fueled protein prenylation pathway in thymocyte egress and immune homeostasis. The protein geranylgeranyltransferase Pggt1b is up-regulated in single-positive thymocytes, and loss of Pggt1b leads to marked defects in thymocyte egress and T cell lymphopenia in peripheral lymphoid organs in vivo. Mechanistically, Pggt1b bridges sphingosine-1-phosphate and chemokine-induced migratory signals with the activation of Cdc42 and Pak signaling and mevalonate-dependent thymocyte trafficking. In contrast, the farnesyltransferase Fntb, which mediates a biochemically similar process of protein farnesylation, is dispensable for thymocyte egress but contributes to peripheral T cell homeostasis. Collectively, our studies establish context-dependent effects of protein prenylation and unique roles of geranylgeranylation in thymic egress and highlight that the interplay between cellular metabolism and posttranslational modification underlies immune homeostasis.
胸腺细胞迁出是 T 细胞稳态和适应性免疫的关键决定因素。尽管 G 蛋白偶联受体在胸腺细胞迁出中起作用，但下游信号机制仍未得到明确界定。在这里，我们报告了甲羟戊酸代谢途径驱动的蛋白质异戊烯化途径的两个分支在胸腺细胞迁出和免疫稳态中的离散作用。蛋白 geranylgeranyltransferase Pggt1b 在单阳性胸腺细胞中上调，并且 Pggt1b 的缺失导致体内外周淋巴器官中胸腺细胞迁出和 T 细胞淋巴细胞减少的明显缺陷。在机制上，Pggt1b 通过与 Cdc42 和 Pak 信号的激活以及甲羟戊酸依赖性胸腺细胞迁移相桥接鞘氨醇-1-磷酸和趋化因子诱导的迁移信号。相比之下，farnesyltransferase Fntb 介导了一种生化上相似的蛋白质法尼基化过程，对于胸腺细胞迁出是可有可无的，但有助于外周 T 细胞的稳态。总之，我们的研究确立了蛋白质异戊烯化的上下文相关效应以及 geranylgeranylation 在胸腺细胞迁出中的独特作用，并强调了细胞代谢和翻译后修饰之间的相互作用是免疫稳态的基础。
