The role of mechanistic target of rapamycin (mTOR) complexes signaling in the immune responses.

Ghada A Soliman

doi:10.3390/nu5062231

Abstract

The mechanistic Target of Rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase which is a member of the PI3K related kinase (PIKK) family. mTOR emerged as a central node in cellular metabolism, cell growth, and differentiation, as well as cancer metabolism. mTOR senses the nutrients, energy, insulin, growth factors, and environmental cues and transmits signals to downstream targets to effectuate the cellular and metabolic response. Recently, mTOR was also implicated in the regulation of both the innate and adaptive immune responses. This paper will summarize the current knowledge of mTOR, as related to the immune microenvironment and immune responses.

Highlights

The evolutionarily conserved mechanistic Target of Rapamycin protein kinase plays an integral role in the coordination of metabolism, protein synthesis, cell growth, and proliferation [1,2,3,4,5]. mTOR serine/threonine kinase functions as a molecular sensor of metabolism and cellular homeostasis and integrates environmental signals by altering the cellular metabolic processes [5,6]
Compelling evidence revealed that the dysregulation of mTOR is linked to the development of chronic diseases including insulin resistance, diabetes, cardiovascular disease, and obesity [17]; as well as progression of various types of cancer [18,19]
It is currently known that mTOR Complex 1 (mTORC1) phosphorylates two well characterized downstream targets, S6 Kinase 1 (S6K1) and 4E-BP1, positive and negative regulators of protein synthesis, respectively (Figure 1)

Summary

Introduction

The evolutionarily conserved mechanistic Target of Rapamycin (mTOR, formerly known as mammalian TOR) protein kinase plays an integral role in the coordination of metabolism, protein synthesis, cell growth, and proliferation [1,2,3,4,5]. mTOR serine/threonine kinase functions as a molecular sensor of metabolism and cellular homeostasis and integrates environmental signals by altering the cellular metabolic processes [5,6]. MTOR forms at least two complexes with the newly identified exclusive as well as common binding partners as shown below (Figure 2) These complexes include rapamycin-sensitive complex (mTORC1) encompassing mTOR, raptor, mLST8, PRAS40, and deptor and rapamycin-insensitive complex (mTORC2), which contains mTOR, rictor, mLST8, mSIN1, protor, and deptor (but not raptor). MTORC1 integrates multiple inputs from signaling pathways including insulin, growth factors, energy, stress, mitogens, and amino acids. MTORC1 comprises mTOR kinase, mTOR-raptor binding partner (raptor), and mLST8, DEPTOR, and PRAS 40; and integrates signals from nutrients, insulin, growth factors, and energy levels, thereby activates downstream targets to control metabolism and cell growth [40,41].While mTORC1 is a nutrient-sensitive pathway, mTORC2 receives inputs only from growth factors, mTORC2 upstream regulation is largely unknown [42]. It has been postulated that rapamycin inhibits T cell proliferation and causes immunosuppression due to its ability to promote T Cell anergy [25,49,50,51]

Downstream of mTOR

Pharmacological Inhibition of mTOR

Conclusions