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Review
. 2019 Jun;19(6):1614-1621.
doi: 10.1111/ajt.15320. Epub 2019 Mar 19.

The "other" mTOR complex: New insights into mTORC2 immunobiology and their implications

Helong Dai  1   2 , Angus W Thomson  1   3
Affiliations
Review

The "other" mTOR complex: New insights into mTORC2 immunobiology and their implications

Helong Dai et al. Am J Transplant. 2019 Jun.

Abstract

A central role of the mechanistic target of rapamycin (mTOR) in regulation of fundamental cell processes is well recognized. mTOR functions in two distinct complexes: rapamycin-sensitive mTOR complex (C) 1 and rapamycin-insensitive mTORC2. While the role of mTORC1 in shaping immune responses, including transplant rejection, and the influence of its antagonism in promoting allograft tolerance have been studied extensively using rapamycin, lack of selective small molecule inhibitors has limited understanding of mTORC2 biology. Within the past few years, however, intracellular localization of mTORC2, its contribution to mitochondrial fitness, cell metabolism, cytoskeletal modeling and cell migration, and its role in differentiation and function of immune cells have been described. Studies in mTORC2 knockdown/knockout mouse models and a new class of dual mTORC1/2 inhibitors, have shed light on the immune regulatory functions of mTORC2. These include regulation of antigen-presenting cell, NK cell, T cell subset, and B cell differentiation and function. mTORC2 has been implicated in regulation of ischemia/reperfusion injury and graft rejection. Potential therapeutic benefits of antagonizing mTORC2 to inhibit chronic rejection have also been described, while selective in vivo targeting strategies using nanotechnology have been developed. We briefly review and discuss these developments and their implications.

Keywords: basic (laboratory) research/science; cellular biology; immunobiology; immunosuppressant - mechanistic target of rapamycin (mTOR); innate immunity; lymphocyte biology; molecular biology; tissue injury and repair; translational research/science.

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Conflict of interest statement

DISCLOSURE

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Figures

Figure 1.
Figure 1.
Biology of mTORC2. mTORC2 consists of several components, including mTOR, Rictor, Protor, Deptor, mSIN1 and mLST8. In contrast, mTORC1 consists of mTOR, Raptor, PRAS40, Deptor and mLST8. mTORC2 has been localized in both cell membrane and intracellular compartments, including mitochondria and endosomal vesicles. PtdIns(3,4,5) P3, plasma membrane tension and growth factors, including insulin, can activate mTORC2. Active mTORC2 phosphorylates multiple protein kinase (PK) PKA, PKC, and PKG family kinases, including Akt, PKCα and SGK1 to support cell growth and survival. Rapamycin inhibits mTORC1 through binding to the immunophilin FKBP12. mTORC2 has been described as insensitive to rapamycin (sirolimus). mTORC2 signaling is also regulated by mTORC1 through a negative feedback loop between mTORC1-S6K1 and insulin/PI3K signaling.
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