mTORC2: The other mTOR in autophagy regulation

Abstract

The mechanistic target of rapamycin (mTOR) has gathered significant attention as a ubiquitously expressed multimeric kinase with key implications for cell growth, proliferation, and survival. This kinase forms the central core of two distinct complexes, mTORC1 and mTORC2, which share the ability of integrating environmental, nutritional, and hormonal cues but which regulate separate molecular pathways that result in different cellular responses. Particularly, mTORC1 has been described as a major negative regulator of endosomal biogenesis and autophagy, a catabolic process that degrades intracellular components and organelles within the lysosomes and is thought to play a key role in human health and disease. In contrast, the role of mTORC2 in the regulation of autophagy has been considerably less studied despite mounting evidence this complex may regulate autophagy in a different and perhaps complementary manner to that of mTORC1. Genetic ablation of unique subunits is currently being utilized to study the differential effects of the two mTOR complexes. RICTOR is the best-described subunit specific to mTORC2 and as such has become a useful tool for investigating the specific actions of this complex. The development of complex-specific inhibitors for mTORC2 is also an area of intense interest. Studies to date have demonstrated that mTORC1/2 complexes each signal to a variety of exclusive downstream molecules with distinct biological roles. Pinpointing the particular effects of these downstream effectors is crucial toward the development of novel therapies aimed at accurately modulating autophagy in the context of human aging and disease.

Keywords: AKT; FOXOs; SGK-1; autophagy; mTORC2.

FIGURE 1

The two distinct mTORC1/2 complexes and their regulation of autophagy. PIKK and DEPTOR are components common to both mTOR complexes, whereas RAPTOR and PRAS40 are specific to mTORC1 and RICTOR and mSIN1 are specific to mTORC2. mTORC1 has been shown to induce phosphorylation of the MiT‐TFE factors, ATG13 and ULK1, which become unable to positively regulate autophagy. In turn, mTORC2 induces the phosphorylation of Beclin‐1, GFAP, and VDAC1, and similarly, prevents them from activating autophagy. mTORC2‐mediated phosphorylation of FOXO proteins modulates their subcellular localization leading to various outcomes regarding autophagy regulation (see Figure 3). See details in text

FIGURE 2

The mTORC2‐AKT‐SGK axis in autophagy. mTORC2 phosphorylates Ser473 of AKT, whereas GSK3b prevents this through an inhibitory phosphorylation of RICTOR. In turn, the phosphatase PHLPP1 can remove the phosphorylation of Ser473 in AKT. pAKT at Ser473 can place inhibitory phosphorylations on Ser234/Ser295 of Beclin‐1 and Ser253/Thr32 of FoxO3, which interferes with the role of these two proteins in the positive modulation of autophagy. pAKT at Ser473 also phosphorylates and inhibits GFAP, resulting in negative regulation of LAMP2A‐mediated CMA. mTORC2 phosphorylates Ser422 of SGK‐1 which, in turn, phosphorylates Thr32 of FoxO3 and Ser104 of VDAC1. pFoxO3 does not participate in the transcriptional upregulation of autophagy and it is believed to reduce the expression of ULK1 and further inhibit autophagy. SGK‐1‐mediated inhibitory phosphorylation of VDAC1 reduces autophagy, mitophagy, and associated mitochondrial permeability

FIGURE 3

mTORC2‐mediated regulation of FoxO1/3 subcellular localization and activity in autophagy. mTORC2‐mediated phosphorylation of Ser473 in AKT triggers the phosphorylation of Thr24 in FoxO1 and its equivalent Thr32 in FoxO3. mTORC2 phosphorylates and inactivates the deacetylase HDAC contributing to the acetylation of FoxO1/3. Similarly, mTORC2 directly interacts with SIRT6 and inhibits its deacetylase activity on FoxO1/3. Independently of mTORC2, FoxO1/3 is acetylated by p300 and deacetylated by SIRT1/2. Phosphorylation and/or acetylation of FoxO1/3 promote their cytoplasmic retention and interaction with ATG7 which has a role in inducing autophagy. In contrast, dephosphorylated and deacetylated FoxO1/3 are readily transported in the nucleus where they stimulate the transcription of autophagy‐related genes