Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

Ananieva, Elitsa; Patel, Chirag H.; Drake, Charles H.; Powell, Jonathan D.; Hutson, Susan M.

doi:10.1074/jbc.m114.554113

Cited by 75 publications

(89 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Leucine can activate mTOR via leucyl-tRNA synthetase [52], thus low concentrations of intracellular leucine can impair mTOR activation. Accordingly it was shown that expression of cytosolic branched chain aminotransferase (BCATc), which transaminates leucine, regulates mTOR activity following T cell activation in a process that limits mTOR over activation [53]. Interestingly, it was found that BCATc is increased in anergic cells.…”

Section: The Basics Of T Cell Metabolismmentioning

confidence: 99%

Targeting T cell metabolism for therapy

O’Sullivan

Pearce

2015

Trends in Immunology

208

169

View full text Add to dashboard Cite

In the past several years, a wealth of evidence has emerged illustrating how metabolism supports many aspects of T cell biology, as well as how metabolic changes drive T cell differentiation and fate. Here we outline developing principles in the regulation of T cell metabolism, and discuss how these processes are impacted in settings of inflammation and cancer. In this context we discuss how metabolic pathways might be manipulated for the treatment of human disease, including how metabolism may be targeted to prevent T cell dysfunction in inhospitable microenvironments, to generate more effective adoptive cellular immunotherapies in cancer, and to direct T cell differentiation and function towards non-pathogenic phenotypes in settings of autoimmunity.

show abstract

Section: The Basics Of T Cell Metabolismmentioning

confidence: 99%

Targeting T cell metabolism for therapy

O’Sullivan

Pearce

2015

Trends in Immunology

208

169

View full text Add to dashboard Cite

show abstract

“…In this regard, leucine appears to be an important nutrient signal that is sensed by the immune cells via mTOR pathway and is critical for their proliferation. Leucine supply to mTOR pathway is regulated through BCAA metabolism as shown recently in T cells [90] . The cytoplasmic branched chain aminotransferase (BCATc), that catalyzes leucine transamination, was induced in activated T cells, where Ananieva E. Amino acid metabolism and cancer it regulated leucine supply to complex 1 of the mTOR pathway.…”

Section: Emerging Role Of Branched Chain Amino Acid Metabolism In Canmentioning

confidence: 99%

“…The cytoplasmic branched chain aminotransferase (BCATc), that catalyzes leucine transamination, was induced in activated T cells, where Ananieva E. Amino acid metabolism and cancer it regulated leucine supply to complex 1 of the mTOR pathway. Loss of BCATc expression eliminated cytosolic leucine catabolism leading to upregulation of complex 1 of the mTOR pathway and increased glycolysis [90] . While mTOR pathway is upregulated in many cancer types and mTOR-targeted cancer therapy has been a part of clinical research [91] , a direct link between mTOR pathway and leucine/BCAA metabolism in the tumor microenvironment awaits to be explored.…”

Section: Emerging Role Of Branched Chain Amino Acid Metabolism In Canmentioning

confidence: 99%

Targeting amino acid metabolism in cancer growth and anti-tumor immune response

Ananieva

2015

WJBC

136

104

View full text Add to dashboard Cite

Recent advances in amino acid metabolism have revealed that targeting amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. There are currently several drugs in clinical trials that specifically target amino acid metabolic pathways in tumor cells. In the context of the tumor microenvironment, however, tumor cells form metabolic relationships with immune cells, and they often compete for common nutrients. Many tumors evolved to escape immune surveillance by taking advantage of their metabolic flexibility and redirecting nutrients for their own advantage. This review outlines the most recent advances in targeting amino acid metabolic pathways in cancer therapy while giving consideration to the impact these pathways may have on the anti-tumor immune response. Core tip: Amino acid metabolism has been a focus of increased attention by cancer researchers and immunologists due to its importance for the metabolic reprogramming of proliferating cells. Many amino acid enzymes are described as immunosuppressive in the tumor microenvironment and targeted for cancer therapy. This review addresses the metabolic control of tumor progression in the context of anti-tumor immunity and discusses current and future therapeutic approaches. Special emphasis is given to the emerging role of branched chain amino acid metabolism in cancer and immunity highlighting some recent work by our research group. Ananieva E. Targeting amino acid metabolism in cancer growth and anti-tumor immune response. World J Biol Chem 2015; 6(4): 281-289 Available from:

show abstract

“…The importance of leucine abundance on the regulation of mTORC1 activity in T lymphocytes is further highlighted by studies in mice lacking the leucine metabolizing enzyme BCATc (cytosolic branched-chain aminotransferase). Activated T cells from these mice have higher intracellular leucine concentrations and show increased mTORC1 activity compared to WT controls [69]. While the data clearly shows that leucine is essential for mTORC1 activity in immune cells, the evidence for a similar sensitivity to arginine is lacking.…”

Section: Amino Acids and Mtorc1mentioning

confidence: 57%

Nutrient sensing, signal transduction and immune responses

Walls

Sinclair

Finlay

2016

Seminars in Immunology

View full text Add to dashboard Cite

Most cells in the body have a constant supply of nutrients, which are required to sustain cellular metabolism and functions. In contrast, cells of the immune system can encounter conditions with a limited nutrient supply during the course of an immune response. Cells of the immune system frequently operate in complex nutrient restricted microenvironments such as tumour or inflammatory sites. The concentrations of key nutrients such as glucose and certain amino acids, can be low at these sites, and this can have an impact upon immune cell function. Nutrient sufficiency is important to supply the metabolic and biosynthetic pathways of immune cells. In addition nutrients can also act as important cues that influence immunological signalling pathways to affect the function of immune cells. This review will describe the various nutrient sensing signalling pathways and discuss the evidence that nutrients are critical signals that shape immune responses.

show abstract

Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

Cited by 75 publications

References 67 publications

Targeting T cell metabolism for therapy

Targeting T cell metabolism for therapy

Targeting amino acid metabolism in cancer growth and anti-tumor immune response

Nutrient sensing, signal transduction and immune responses

Contact Info

Product

Resources

About