Crosstalk of the Caspase Family and Mammalian Target of Rapamycin Signaling

Abstract

Cell can integrate the caspase family and mammalian target of rapamycin (mTOR) signaling in response to cellular stress triggered by environment. It is necessary here to elucidate the direct response and interaction mechanism between the two signaling pathways in regulating cell survival and determining cell fate under cellular stress. Members of the caspase family are crucial regulators of inflammation, endoplasmic reticulum stress response and apoptosis. mTOR signaling is known to mediate cell growth, nutrition and metabolism. For instance, over-nutrition can cause the hyperactivation of mTOR signaling, which is associated with diabetes. Nutrition deprivation can inhibit mTOR signaling via SH3 domain-binding protein 4. It is striking that Ras GTPase-activating protein 1 is found to mediate cell survival in a caspase-dependent manner against increasing cellular stress, which describes a new model of apoptosis. The components of mTOR signaling-raptor can be cleaved by caspases to control cell growth. In addition, mTOR is identified to coordinate the defense process of the immune system by suppressing the vitality of caspase-1 or regulating other interferon regulatory factors. The present review discusses the roles of the caspase family or mTOR pathway against cellular stress and generalizes their interplay mechanism in cell fate determination.

Keywords: cell fate; interplay; mTOR signaling; the caspase family.

Figure 1

Apoptosis, inflammation and endoplasmic reticulum (ER) stress regulated by the caspase family. Stress stimulation such as DNA damage can trigger intrinsic apoptosis, in which releasing cytochrome c activates the complex of apoptosis-activating factor 1 (Apaf-1) and caspase-9, initiating the auto-activation of caspase-9. The binding of cell surface death ligand and receptors induces extrinsic apoptosis, and caspase-8 or caspase-10 are the initiator caspases. Caspase-3, -6 and -7 execute apoptosis effector of both apoptosis pathways to catalyze a variety of key cellular substrates. Death stimulations restrain anti-apoptotic members of the Bcl-2 subfamily through the pro-apoptotic factors BH3 subfamily and then activate the pro-apoptotic factors Bax subfamily, functioning as the co-factor of caspases. The central member of the caspases in response to the inflammation is caspase-1. Inflammasome sensors (The nucleotide-binding domain and leucine-rich repeat containing (NLR) family, the HIN200 family member absent in melanoma 2 (AIM2) and the TRIM family member Pyrin) identify the inflammatory irritants such as pathogens and activate caspase-1 by forming a complex with the adaptor protein apoptosis associated speck like protein containing a CARD (ASC) and caspase-1 to promote the maturation and secretion of IL-1β and IL-18 in the canonical inflammasome pathway. Caspase-4, -5 and -11 respond to lipopolysaccharide arising from Gram-negative bacterial infection with the non-canonical inflammasome pathway. Finally, severe inflammations lead to apoptosis. ER stress response is mediated by caspase-4, -5, -8 and -12 with different mechanisms to induce inflammation and apoptosis. Inositol-requiring enzyme 1 (IRE1α) and PKR-like ER kinase (PERK) are the transmembrane sensors of ER. The Human transmembrane protein 214 (TMEM214) locates at the upstream of caspase-4.

Figure 2

The response model of Ras/phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway to the growth factors, amino acids and glucose levels. mTORC1 and mTORC2 are the two distinct multiprotein complexes of mTOR in function and biochemistry. The mTORC1 complex consists of mTOR, GβL and raptor. The mTORC2 complex is comprised of mTOR, GβL and rictor. The two mTOR complexes have a central role in different kinds of environmental stimulations. Upon the growth factors response, the bindings of ligands and receptors activate Ras and PI3K. PI3K can be activated by both receptor and activated Ras. Active PI3K transfers phosphate groups to phosphatidylinositol 4, 5-bisphosphate (PIP2) and generate phosphatidylinositol 3, 4, 5-triphosphate (PIP3) to recruit PDK1 (phosphorylates Akt on Thr 308) and mTORC2 (phosphorylates Akt on Ser 473). The Akt suppresses TSC-TBC1D7 (TSC-TBC) and promotes Rheb to activate mTORC1 to regulate cell growth by targeting ribosomal S6 protein (S6K1) and eukaryotic translational initiation factor eIF4E-binding protein 1 (4E-BP1). Under the normal nutrition, the amino acids and glucose are absorbed by a nutrisome complex that includes proton-assisted SLC36 AA transporters (PATs), Ras-related GTPase (Rag), Ragulator and v-ATPase to activate the mTORC1. Nutrition deprivation negatively mediates the activation of mTORC1 through the binding between domain binding protein 4 (SH3BP4) and Rag. In the case of over-activation of nutrition, inactive Enoyl-CoA hydratase 1 (ECHS1) by acetylation activates mTOR. There is a negative feedback regulatory mechanism to maintain nutrition balance. mTORC1 can cause inhibition of insulin receptor substrate-1 (IRS-1) Ser 636/639 phosphorylation under over-nutrition, and further restrain PI3K/Akt signaling. The liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway is a negative regulator of mTORC1.

Figure 3

Regulation of mTOR signaling for the caspase family. mTOR signal transduction mediates the caspase family in terms of cell survival and inflammation in a direct and indirect manner. Akt can directly phosphorylate caspase-9 (Ser 196) and Bad (Ser 136), resulting in the limiting of cell survival. The function mechanisms of inhibitors (rapamycin and KNK437) and agonist (propofol) of mTOR indicate that the Bcl-2 family play roles as connectors of mTOR signaling and caspases. In addition, mTOR can inhibit the activation of caspase-1 and mediate the transcription of cytokine via MyD88/IRF-5/IRF-7 to affect inflammation and immunity.

Figure 4

The new model of apoptosis regulated by the caspase-dependent cleavage of mTOR and Ras GTPase-activating protein 1 (RasGAP). Human raptor can be cleaved into N-terminus and C-terminus by active recombinant caspase-1, -3 and -6 in vitro. This cleavage of raptor is similar to the inhibition mechanism induced by rapamycin, which disturbs the interaction of raptor and mTOR. The binding of growth factors and receptor recruits adaptor proteins containing the SRC homology domain 2 (SH2) or phosphotyrosine binding domains such as growth factor receptor-bound protein 2 (GRB2). Son of seven less homolog protein (SOS) is subsequently activated and stimulates the exchange of GDP for GTP on Ras. In contrast, RasGAP catalyzes GTP hydrogenation and maintains Ras in the inactive GDP-bound state. The cleavage sites of RasGAP induced by caspase-3 contain 455 aspartic acid and 157 aspartic acid position. The low activity of caspase-3 cleaves the RasGAP into fragment N and fragment C at region 455. Fragment N can achieve cell protection, and fragment C induces apoptosis, which is restrained by fragment N. With the increasing of caspase-3 activity, site 157 is cleaved and generates fragment N1 and fragment N2, which contribute to cell death by blocking the phosphorylation of Akt at Ser 473. This is a new model for the regulation of apoptosis.