mTORC1 signaling and IL‐17 expression: Defining pathways and possible therapeutic targets

Abstract

IL-17 mediates immune responses against extracellular pathogens, and it is associated with the development and pathogenesis of various autoimmune diseases. The expression of IL-17 is regulated by various intracellular signaling cascades. Recently, it hasbeen shown that mechanistic target of rapamycin (mTOR) signaling, comprised mainly of mTORC1 signaling, plays a critical role in IL-17 expression. Here, we review the current knowledge regarding mechanisms by which mTORC1 regulates IL-17 expression. mTORC1 positively modulates IL-17 expression through several pathways, i.e. STAT3, -HIF-1α, -S6K1, and -S6K2. Amino acids (AAs) also regulate IL-17 expression by being the energy source for Th17 cells, and by activating mTORC1 signaling. Altogether, the AA-mTORC1-IL-17 axis has broad therapeutic implications for IL-17-associated diseases, such as EAE, allergies, and colitis. Keywords: Amino acid IL-17 mTORC1 STAT HIF-1α IntroductionMechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine protein kinase that integrates diverse environmental signals (i.e. hormones, growth factors, and amino acids) into appropriate cellular metabolism and responses to maintain cellular homeostasis [1]. mTOR refers to two complexes, the mTOR complex 1 (mTORC1) and the mTOR complex 2 (mTORC2), which differ in composition, substrates metabolized, and cellular functions ( Fig. 1) [2, 3]. mTORC1 is composed of mTOR, raptor (regulatory-associated protein of mTOR) [4, 5], mLST8/GβL (mammalian lethal with Correspondence: Prof. Yulong Yin e-mail: yinyulong@isa.ac.cn Sec 13 protein 8/G-protein β-protein subunit like) [6], PRAS40 (Akt/PKB substrate 40kDa) [7, 8], and deptor (DEP-domaincontaining mTOR interacting protein) [9] (Fig. 1A). Raptor recruits substrates to the mTOR kinase through TOS (TOR signaling) motifs on the substrates [10, 11], and PRAS40 and deptor are suppressors and targets of mTORC1, potentially acting as competitive substrates [9, 12]. Interestingly, mLST8/GβL does not appear to be essential for mTORC1 function based on evidence that: (i) unlike the absence of raptor or mTOR in mice, which results in early embryonic lethality (around embryonic day (e) 5.5 [13, 14], mLST8 null mouse embryos survive until e10.5 [14]; and (ii) mLST8 is not necessary to maintain the raptor-mTOR interaction and the phosphorylation of ribosomal S6 kinase 1 (S6K1) [14]. mTORC1 has numerous downstream effectors, including S6Ks, 4EBPs, IRS-1, ULK1, Lipin1, TFEB, and GRB10 [1,15,16]. Through these substrates, the activation of mTORC1 signalingwww.eji-journal.eu 292Wenkai Ren et al. Eur. J. Immunol. 2016. 46: 291-299 Figure 1. Components, substrates, and cellular functions of mTORC1 and mTORC2. (A) mTORC1 is composed of mTOR, raptor, mLST8/GβL, PRAS40, and deptor. mTORC1 promotes protein, lipid, and nucleotide synthesis, cell growth, and proliferation, and inhibition of autophagy through numerous downstream effectors, including S6Ks, 4EBPs, IRS-1, ULK1, Lipin1, TFEB, and GRB10. (B) mTORC2 is composed of mTOR, rictor, mS...

Amino Acid Catabolism in Multiple Sclerosis Affects Immune Homeostasis

“…Supporting these findings, GNC2-deficient mice develop a form of EAE characterized by absence of remission (52). In contrast, the mTORC1 pathway regulates metabolic programs to facilitate the switch from quiescent to activated T cell and plays a critical role in Th17 cell differentiation (53,54). Meanwhile, mTORC2 through its substrate SGK1 regulates the ability of Th cells to differentiate into Th2 cells (55,56).…”

Interferon Tau Affects Mouse Intestinal Microbiota and Expression of IL-17

“…IL-17 can activate nuclear factor κ B (NF- κ B) transcription factors, extracellular signal-regulated protein kinase (ERK1 and ERK2), c-Jun N-terminal kinases (JNK-1 and JNK-2), and mitogen-activated protein kinases (p38 MAPKs) pathways, leading to upregulation of expression of inflammatory cytokines, such as IL-6 and IL-1 [32]. Recent investigations have revealed that mammalian target of rapamycin (mTOR) is a critical signaling pathway for Th17 responses and IL-17 expression [33–37]. The mTOR signaling regulates IL-17 expression through hypoxia-inducible factor 1 α (HIF-1 α ) and ribosomal protein S6 kinase (S6K: S6K1 and S6K2) [37–40].…”

“…Recent investigations have revealed that mammalian target of rapamycin (mTOR) is a critical signaling pathway for Th17 responses and IL-17 expression [33–37]. The mTOR signaling regulates IL-17 expression through hypoxia-inducible factor 1 α (HIF-1 α ) and ribosomal protein S6 kinase (S6K: S6K1 and S6K2) [37–40]. mTOR signaling activates HIF-1 α , which promotes IL-17 expression by activating ROR γ t (a key transcriptional regulator of Th17 cells) and mediating degradation of Foxp3 (a key transcriptional regulator of Treg cells) [40].…”

“…mTOR signaling activates HIF-1 α , which promotes IL-17 expression by activating ROR γ t (a key transcriptional regulator of Th17 cells) and mediating degradation of Foxp3 (a key transcriptional regulator of Treg cells) [40]. S6K1 promotes the expression of early growth response protein 2 (EGR2), which then inhibits growth factor independent 1 transcription repressor (GFI1), which can negatively regulate expression of IL-17 without affecting Rorc expression [37, 38]. S6K2 (the nuclear-localized counterpart of S6K1) binds to ROR γ t to promote nuclear translocation of ROR γ t, which can complex with HIF- α and p300 in the nucleus to promote expression of IL-17 [37–39].…”

The Magnitude of mTORC1 Signalling May Predict the Response to Isotretinoin Treatment in Patients with Hidradenitis Suppurativa

“…The mTORC1 pathway is of pivotal importance for metabolic regulation and functioning of innate and adaptive immune cells, as clearly verified by the immunesuppressive function of mTORC1 inhibitors such as rapamycin [7]. Notably, the differentiation of Th17 cells is controlled by mTORC1, which promotes Th17 differentiation [8,9]. Moran et al [10] recently confirmed substantial infiltration of inflammatory Th17 cells with a striking Th17-skewed cytokine profile in HS skin.…”