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Histone acetyltransferase CBP is critical for conventional effector and memory T-cell differentiation in mice.

ABSTRACT: Compared with naïve T cells, memory CD8+ T cells have a transcriptional landscape and proteome that are optimized to generate a more rapid and robust response to secondary infection. Additionally, rewired kinase signal transduction pathways likely contribute to the superior recall response of memory CD8+ T cells, but this idea has not been experimentally confirmed. Herein, we utilized an MS approach to identify proteins that are phosphorylated on tyrosine residues in response to Listeria-induced T-cell receptor (TCR) stimulation in both naïve and memory CD8+ T cells from mice and separated by fluorescence- and flow cytometry-based cell sorting. This analysis identified substantial differences in tyrosine kinase signaling networks between naïve and memory CD8+ T cells. We also observed that an important axis in memory CD8+ T cells couples Janus kinase 2 (JAK2) hyperactivation to the phosphorylation of CREB-binding protein (CBP). Functionally, JAK2-catalyzed phosphorylation enabled CBP to bind with higher affinity to acetylated histone peptides, indicating a potential epigenetic mechanism that could contribute to rapid initiation of transcriptional programs in memory CD8+ T cells. Moreover, we found that CBP itself is essential for conventional effector and memory CD8+ T-cell formation. These results indicate how signaling pathways are altered to promote CD8+ memory cell formation and rapid responses to and protection from repeat infections.

SUBMITTER: Piccirillo AR

PROVIDER: S-EPMC6378974 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Histone acetyltransferase CBP is critical for conventional effector and memory T-cell differentiation in mice.

Piccirillo Ann R AR Cattley Richard T RT D'Cruz Louise M LM Hawse William F WF

The Journal of biological chemistry 20181220 7

Compared with naïve T cells, memory CD8<sup>+</sup> T cells have a transcriptional landscape and proteome that are optimized to generate a more rapid and robust response to secondary infection. Additionally, rewired kinase signal transduction pathways likely contribute to the superior recall response of memory CD8<sup>+</sup> T cells, but this idea has not been experimentally confirmed. Herein, we utilized an MS approach to identify proteins that are phosphorylated on tyrosine residues in respon ...[more]

PMID: 30573679

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Project description:CREB (cyclic AMP response element binding protein) binding protein (CBP, CREBBP) is a ubiquitously expressed transcription coactivator with intrinsic histone acetyltransferase (KAT) activity. Germline mutations within the CBP gene are known to cause Rubinstein-Taybi syndrome (RSTS), a developmental disorder characterized by intellectual disability, specific facial features and physical anomalies. Here, we investigate mechanisms of CBP function during brain development in order to elucidate morphological and functional mechanisms underlying the development of RSTS. Due to the embryonic lethality of conventional CBP knockout mice, we employed a tissue specific knockout mouse model (hGFAP-cre::CBPFl/Fl, mutant mouse) to achieve a homozygous deletion of CBP in neural precursor cells of the central nervous system.Our findings suggest that CBP plays a central role in brain size regulation, correct neural cell differentiation and neural precursor cell migration. We provide evidence that CBP is both important for stem cell viability within the ventricular germinal zone during embryonic development and for unhindered establishment of adult neurogenesis. Prominent histological findings in adult animals include a significantly smaller hippocampus with fewer neural stem cells. In the subventricular zone, we observe large cell aggregations at the beginning of the rostral migratory stream due to a migration deficit caused by impaired attraction from the CBP-deficient olfactory bulb. The cerebral cortex of mutant mice is characterized by a shorter dendrite length, a diminished spine number, and a relatively decreased number of mature spines as well as a reduced number of synapses.In conclusion, we provide evidence that CBP is important for neurogenesis, shaping neuronal morphology, neural connectivity and that it is involved in neuronal cell migration. These findings may help to understand the molecular basis of intellectual disability in RSTS patients and may be employed to establish treatment options to improve patients' quality of life.

Dataset Information

Histone acetyltransferase CBP is critical for conventional effector and memory T-cell differentiation in mice.

Publications

Histone acetyltransferase CBP is critical for conventional effector and memory T-cell differentiation in mice.

Similar Datasets

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