Chapter Seven - A most versatile kinase: The catalytic subunit of PKA in T-cell biology

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Abstract

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.

Section snippets

A brief introduction to PKA biology

PKA, which is formally designated as cAMP-dependent protein kinase (EC 2.7.11.11), is a highly promiscuous serine/threonine kinase with over 250 identified substrates (Soberg and Skalhegg, 2018). In the absence of activating stimuli, PKA typically forms a tetrameric holoenzyme consisting of two regulatory subunits (PKAr) that bind and inactivate two catalytic subunits (PKAc). Classical PKA activation results from binding of an extracellular signal, such as prostaglandin E2 (PGE2), to its

PKA as a regulator of NF-κB activity

One of the more enigmatic PKA substrates is the p65 subunit of the transcription factor NF-κB (Zhong et al., 1997). p65 is one of five NF-κB family members, which hold critical roles in the regulation of multiple biological processes including cell survival, differentiation, proliferation, and, in particular, the immune response. The members of the NF-κB family exist as different combinations of homo- and heterodimers, which regulate distinct but overlapping gene sets. The most prevalent of

The role of cAMP and PKA in T cells

Increasing the intracellular concentration of cAMP, and thereby activating PKA, for extended periods of time is generally associated with immunosuppressive effects. In fact, several microbial species, including such important pathogens as Mycobacterium tuberculosis, Bacillus anthracis and Plasmodium falciparum, have evolved mechanisms to increase cAMP levels in host cells to blunt the immune response (McDonough and Rodriguez, 2011). While immunosuppression by cAMP is better understood in innate

The translational relevance of PKA

Only few diseases have been linked to PKA defects, presumably due to the embryonic lethality associated with PKA dysfunction. Important examples include point mutations in PRKACA, which are found frequently in adrenocortical tumors that produce excessive levels of cortisol and thus cause Cushing's syndrome (Beuschlein et al., 2014; Cao et al., 2014; Cheung et al., 2015); a large-scale deletion on chromosome 19 that creates an oncogenic fusion protein of DnaJ B1 and PKAc isoform Cα (DNAJB1-PRKACA

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