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Review
. 2022 Mar;19(3):303-315.
doi: 10.1038/s41423-021-00792-8. Epub 2022 Jan 4.

Protein synthesis, degradation, and energy metabolism in T cell immunity

Julia M Marchingo  1 , Doreen A Cantrell  2
Affiliations
Review

Protein synthesis, degradation, and energy metabolism in T cell immunity

Julia M Marchingo et al. Cell Mol Immunol. 2022 Mar.

Abstract

T cell activation, proliferation, and differentiation into effector and memory states involve massive remodeling of T cell size and molecular content and create a massive increase in demand for energy and amino acids. Protein synthesis is an energy- and resource-demanding process; as such, changes in T cell energy production are intrinsically linked to proteome remodeling. In this review, we discuss how protein synthesis and degradation change over the course of a T cell immune response and the crosstalk between these processes and T cell energy metabolism. We highlight how the use of high-resolution mass spectrometry to analyze T cell proteomes can improve our understanding of how these processes are regulated.

Keywords: Immunometabolism; Protein Translation; Protein degradation; Proteomics; T lymphocyte.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Features of protein synthesis. A Basic schematic of the three major steps in protein synthesis: initiation, elongation, and termination. B A single ribosome recruited to mRNA is referred to as a monosome; when multiple ribosomes are simultaneously recruited to mRNA, the structure is called a polysome. C (Left) The translational repressors eIF4EBP1-3 and PDCD4 can prevent eIF4E and eIF4A, respectively, from binding to the eIF4G scaffold protein. (middle) Schematic of eIF4F recruitment to mRNA. (right) Schematic of the preinitiation complex
Fig. 2
Fig. 2
Protein synthesis and energy production during in vitro and in vivo T cell responses. Changes in amino acid uptake (via purple transporters); glucose uptake (via red transporters); ribosome assembly and protein synthesis; and energy (ATP) production via glycolysis (diagonal 4× arrows) and mitochondrial oxidative phosphorylation (OXPHOS) or fatty acid oxidation (FAO) in A ex vivo naive and in vitro 6 and 24 h TCR-activated T cells; in vivo and in vitro generated B effector T cells; and C memory T cells. A Naive T cells have very low nutrient uptake, protein synthesis, and energy production. T cell activation increases protein synthesis and energy production by increasing nutrient uptake and engaging preformed protein machinery before further increasing the expression of nutrient transporters, metabolic machinery, and ribosomes to support large-scale cell growth. B, C In vivo activated cells maintain a high growth phenotype only while they proliferate, whereas nutrient uptake, energy production, and protein synthesis are reduced when they terminally differentiate into effector or memory T cells. In vitro-generated T cells maintain a high growth phenotype for the entire culture period, with effector (IL2-cultured) T cells exhibiting a higher pro-growth phenotype than memory-like (IL15-cultured) T cells
Fig. 3
Fig. 3
MYC regulation: an example of how feedback among protein synthesis, cell metabolism, and protein degradation controls T cell function. Under high nutrient environments and/or high pro-growth signaling, there are high levels of amino acid and glucose uptake. This fuels high energy (ATP) production, supporting high levels of protein synthesis and the production of UDP-GlcNAc from glutamine and glucose. O-GlcNAcylation at Thr58 stabilizes MYC and prevents its proteasomal degradation. Increased MYC expression promotes the transcription of mRNA for the synthesis of proteins, including amino acid transporters, metabolic enzymes, and ribosomes, thus creating a positive feedforward loop to support a highly biosynthetic environment and sustain high MYC expression. This environment supports the high expression of effector proteins. In contrast, in low nutrient conditions and/or low pro-growth signaling, there is low amino acid and glucose uptake. This results in low energy production and limited fuel and biomolecules for the synthesis of effector proteins. Less MYC is synthesized, and thus, less MYC is O-GlcNAcylated, increasing the proteasomal degradation of MYC. This feedback reduces the MYC-mediated transcription of pro-growth mRNAs
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