Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation

Ron-Harel, Noga; Santos, Daniel; Ghergurovich, Jonathan M.; Sage, Peter T.; Reddy, Anita; Lovitch, Scott B.; Dephoure, Noah; Satterstrom, F. Kyle; Sheffer, Michal; Spinelli, Jessica B.; Gygi, Steven P.; Rabinowitz, Joshua D.; Sharpe, Arlene H.; Haigis, Marcia C.

doi:10.1016/j.cmet.2016.06.007

Cited by 330 publications

(306 citation statements)

References 41 publications

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“…We therefore analyzed mitochondrial shape in T cells at different times after activation ± αCD28. T cells primed (+) αCD28 displayed elongated mitochondria early after activation (Buck et al, 2016; Ron-Harel et al, 2016), whereas T cells primed (−) αCD28 had more spherical mitochondria (Figures 2A and S2A–B). Spherical mitochondria are associated with rapidly dividing glycolytic T cells (Buck et al, 2016), a phenotype observed in mature IL-2 T E cells primed ± αCD28 (Figures 2A and S2B).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Priming by CD28

Geltink

O’Sullivan

Corrado

et al. 2017

Cell

235

201

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SUMMARY T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial FAO, before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation – cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity essential for future T cell responses.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial Priming by CD28

Geltink

O’Sullivan

Corrado

et al. 2017

Cell

235

201

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“…This is met by large changes in gene expression that serve both to mobilize existing stored 1C from 5-formyl-THF by 5-formyltetrahydrofolate cycloligase, and to produce new 1C units from serine via the SHMT2-MTHFD2 pathway (Ron-Harel et al, 2016). Interestingly, inhibition of T cell activation by SHMT2 short hairpin RNA (shRNA) was fully rescued by a combination of formate and the general antioxidant N-acetylcysteine, but not either alone, implicating the mitochondrial 1C pathway in T cells in both 1C unit generation and redox defense, as previously observed in HEK293T cells (Ducker et al, 2016).…”

Section: C Metabolism In Development and Proliferative Adult Tissuesmentioning

confidence: 99%

One-Carbon Metabolism in Health and Disease

2017

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One-carbon (1C) metabolism, mediated by the folate cofactor, supports multiple physiological processes. These include biosynthesis (purines and thymidine), amino acid homeostasis (glycine, serine, and methionine), epigenetic maintenance, and redox defense. Both within eukaryotic cells and across organs, 1C metabolic reactions are compartmentalized. Here we review the fundamentals of mammalian 1C metabolism, including the pathways active in different compartments, cell types, and biological states. Emphasis is given to recent discoveries enabled by modern genetics, analytical chemistry, and isotope tracing. An emerging theme is the biological importance of mitochondrial 1C reactions, both for producing 1C units that are exported to the cytosol and for making additional products, including glycine and NADPH. Increased clarity regarding differential folate pathway usage in cancer, stem cells, development, and adult physiology is reviewed and highlights new opportunities for selective therapeutic intervention.

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“…These results suggest that K280 can be a potential cancer therapy site. SHMT2 is a universal enzyme for cell proliferation and T-cell activation (44). A specific single amino acid mutation technique changing K 280 to E can be used for suppression of SHMT2-related cancer, providing a potential simple tool for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation

et al. 2018

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The mitochondrial serine hydroxymethyltransferase SHMT2, which catalyzes the rate-limiting step in serine catabolism, drives cancer cell proliferation, but how this role is regulated is undefined. Here, we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2, which was crucial for activating its enzymatic activity. Conversely, hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo. Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and to abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth.Significance: These findings reveal a novel mechanism for controlling cancer cell proliferation by blocking serine catabolism, as a general strategy to impede tumor growth. Cancer Res; 78(2); 372-86.Ó2017 AACR.

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Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation

Cited by 330 publications

References 41 publications

Mitochondrial Priming by CD28

Mitochondrial Priming by CD28

One-Carbon Metabolism in Health and Disease

SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation

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