TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging

Abstract

The Target of Rapamycin (TOR or mTOR) is a serine/threonine kinase that regulates growth, development, and behaviors by modulating protein synthesis, autophagy, and multiple other cellular processes in response to changes in nutrients and other cues. Over recent years, TOR has been studied intensively in mammalian cell culture and genetic systems because of its importance in growth, metabolism, cancer, and aging. Through its advantages for unbiased, and high-throughput, genetic and in vivo studies, Caenorhabditis elegans has made major contributions to our understanding of TOR biology. Genetic analyses in the worm have revealed unexpected aspects of TOR functions and regulation, and have the potential to further expand our understanding of how growth and metabolic regulation influence development. In the aging field, C. elegans has played a leading role in revealing the promise of TOR inhibition as a strategy for extending life span, and identifying mechanisms that function upstream and downstream of TOR to influence aging. Here, we review the state of the TOR field in C. elegans, and focus on what we have learned about its functions in development, metabolism, and aging. We discuss knowledge gaps, including the potential pitfalls in translating findings back and forth across organisms, but also describe how TOR is important for C. elegans biology, and how C. elegans work has developed paradigms of great importance for the broader TOR field.

Keywords: Caenorhabditis elegans development; DAF-15; NPRL-2; NPRL-3; Nprl2; Nprl3; RAGA-1; RSKS-1; RagA; RagC; Raptor; Rheb; Rheb-1; Rictor; S6 kinase; TOR; TORC1; TORC2; WormBook; aging; growth regulation; metabolism; nutrient signaling; sphingolipid.

Figure 1

Core components of TOR signaling in C. elegans. (A) Cartoon diagram of the protein structures and domains in LET-363/TOR, DAF-15/Raptor, and RICT-1/Rictor [adapted from Long et al. (2002) and Jia et al. (2004)]. Mutant alleles (h111, h131, h114, and m81) and key conserved residues (Trp2198, Ser2206, and Lys2363) are indicated. HEAT repeats are named for four proteins (Huntingtin, EF3, PP2A, and TOR1) that contain this repeat structure. The RICT-1 domains are less characterized (domain identities taken from InterPro/European Molecular Biology Laboratory-European Bioinformatics Institute). (B) TORC1 is defined as the complex containing LET-363/TOR and DAF-15/Raptor. TORC2 is defined as the complex containing LET-363/TOR and RICT-1/Rictor. It is expected that other proteins are found in these complexes and required for TOR signaling. Please see the text for more discussion. AA, amino acid; FAT, focal adhesion-targeting domain; FATC, focal adhesion-targeting C-terminal domain; FRB, FKBP-Rapamycin-Binding domain (where FKBP stands for FK506-binding protein); RNC, Raptor N-terminal CASPase-like domain; TOR, Target of Rapamycin; TORC, TOR Complex; WD40 repeat, ∼40AA motif that terminates in W-D.

Figure 2

Abbreviated illustration of pathways, or cellular processes, identified to act upstream or downstream of TORC1 (A) and TORC2 (B) in C. elegans. These models are based mainly upon genetic analyses but also incorporate mechanistic findings from other systems. In many cases, C. elegans researchers analyzed the TORC1 or TORC2 function under starvation or dietary restriction conditions, when food/nutrient signals were absent or reduced. Arrows indicate the positive regulation or input, whereas T-bars indicate negative regulation, with neither necessarily indicating direct regulation. Please see the text for more discussion on these pathways and downstream physiological functions. TOR functions are notably complex and wide ranging, extending beyond the canonical functions that have been identified in other organisms. For example, the stress response transcription factor SKN-1 has three different roles regarding the two TOR complexes: it promotes transcription of several TORC1 components, its target genes are activated when TORC1 or translation is inhibited, and it is regulated downstream of TORC2 (see sections Roles of TORC2 in regulating development and behaviors and Life span extension and increased stress resistance from TORC1 inhibition). BCAA, branched-chain AAs; GlcCer, glycosylceramide; IIS, insulin/IGF signaling; mmBCFA, monomethyl branched-chain fatty acid; TOR, Target of Rapamycin; TORC, TOR Complex; VB2, vitamin B2.

Figure 3

Proposed role of intestinal TORC1 in mediating the impact of lipids (A) and vitamin B2 (B) on animal development, and food behavior. Neuronal function related to food behaviors has been linked to the axis in (A) but … expression in (B). BCAA, branched-chain amino acids. mmBCFA, monomethyl branched-chain fatty acids. mmBCFA are derived from BCAA and both can be obtained from diet. BCAA, branched-chain AAs; mmBCFA, monomethyl branched-chain fatty acid; TORC, Target of Rapamycin Complex.

Figure 4

Proposed roles of TORC1 in three specific developmental events. Available experimental evidence supports a site of action for TORC1 in the hypodermis for (A) and in the germline for (B) and (C). IIS, insulin/IGF signaling; TORC, Target of Rapamycin Complex.

Figure 5

Processes through which TORC1 affects C. elegans life span. A partial list of major biological functions through which TORC1 modulates life span is shown. The critical role of TORC1 in dietary restriction is indicated, but TORC1 is also involved in other pathways that promote longevity. Please see the text for a more thorough discussion. ECM, extracellular matrix; TORC, Target of Rapamycin Complex.

Figure 6

Regulatory mechanisms through which TOR signaling affects C. elegans life span. A partial list of transcription regulators through which TOR signaling affects life span is shown. Note the potential cross talk between TOR signaling and IIS that has been suggested by genetic analyses in C. elegans, and mechanistic studies in other species. Please see the text for a more thorough discussion. Pol, polymerase; TOR, Target of Rapamycin; TORC, TOR Complex.

Figure 7

Processes through which TORC2 affects C. elegans life span. Three distinct pathways have been described through which TORC2 and SGK-1 influence life span. Whether life span is increased or decreased depends upon the balance among these mechanisms. Please see the text for a more thorough discussion. TORC, Target of Rapamycin Complex.