Department of Microbiology & Immunology, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY, United States.
Int Rev Cell Mol Biol. 2021;361:301-318. doi: 10.1016/bs.ircmb.2021.01.005. Epub 2021 Jan 27.
The cAMP-dependent protein kinase, more commonly referred to as protein kinase A (PKA), is one of the most-studied enzymes in biology. PKA is ubiquitously expressed in mammalian cells, can be activated in response to a plethora of biological stimuli, and phosphorylates more than 250 known substrates. Indeed, PKA is of central importance to a wide range of organismal processes, including energy homeostasis, memory formation and immunity. It serves as the primary effector of the second-messenger molecule 3',5'-cyclic adenosine monophosphate (cAMP), which is believed to have mostly inhibitory effects on the adaptive immune response. In particular, elevated levels of intracellular cAMP inhibit the activation of conventional T cells by limiting signal transduction through the T-cell receptor and altering gene expression, primarily in a PKA-dependent manner. Regulatory T cells have been shown to increase the cAMP levels in adjacent T cells by direct and indirect means, but the role of cAMP within regulatory T cells themselves remains incompletely understood. Paradoxically, cAMP has been implicated in promoting T-cell activation as well, adding another functional dimension beyond its established immunosuppressive effects. Furthermore, PKA can phosphorylate the NF-κB subunit p65, a transcription factor that is essential for T-cell activation, independently of cAMP. This phosphorylation of p65 drastically enhances NF-κB-dependent transcription and thus is likely to facilitate immune activation. How these immunosuppressive and immune-activating properties of PKA balance in vivo remains to be elucidated. This review provides a brief overview of PKA regulation, its ability to affect NF-κB activation, and its diverse functions in T-cell biology.
环腺苷酸（cAMP）依赖性蛋白激酶，通常被称为蛋白激酶 A（PKA），是生物学中研究最广泛的酶之一。PKA 在哺乳动物细胞中广泛表达，可以对多种生物刺激做出反应，并磷酸化 250 多种已知的底物。事实上，PKA 对广泛的生物过程至关重要，包括能量稳态、记忆形成和免疫。它是第二信使分子 3'，5'-环腺苷酸（cAMP）的主要效应物，cAMP 被认为对适应性免疫反应主要具有抑制作用。特别是，细胞内 cAMP 水平的升高通过限制 T 细胞受体的信号转导并改变基因表达，主要以 PKA 依赖的方式抑制常规 T 细胞的激活。已经表明调节性 T 细胞通过直接和间接的方式增加相邻 T 细胞中的 cAMP 水平，但调节性 T 细胞本身内 cAMP 的作用仍不完全清楚。矛盾的是，cAMP 也被牵连到促进 T 细胞激活中，除了其已建立的免疫抑制作用之外，还增加了另一个功能维度。此外，PKA 可以磷酸化 NF-κB 亚基 p65，p65 是 T 细胞激活所必需的转录因子，与 cAMP 无关。这种 p65 的磷酸化极大地增强了 NF-κB 依赖性转录，因此很可能促进免疫激活。PKA 的这些免疫抑制和免疫激活特性如何在体内达到平衡仍有待阐明。本综述简要概述了 PKA 的调节、其影响 NF-κB 激活的能力以及其在 T 细胞生物学中的多种功能。
