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Title: CAMKII and Calcineurin regulate the lifespan of Caenorhabditis elegans through the FOXO transcription factor DAF-16}
Article:
Abstract:
The insulin-like signaling pathway maintains a relatively short wild-type lifespan in Caenorhabditis elegans by phosphorylating and inactivating DAF-16, the ortholog of the FOXO transcription factors of mammalian cells. DAF-16 is phosphorylated by the AKT kinases, preventing its nuclear translocation. Calcineurin( PP2B phosphatase) also limits the lifespan of C. elegans, but the mechanism through which it does so is unknown. Herein, we show that TAX-6•CNB-1 and UNC-43, the C. elegans Calcineurin and Ca2+/calmodulin-dependent kinase type II( CAMKII) orthologs, respectively, also regulate lifespan through DAF-16. Moreover, UNC-43 regulates DAF-16 in response to various stress conditions, including starvation, heat or oxidative stress, and cooperatively contributes to lifespan regulation by insulin signaling. However, unlike insulin signaling, UNC-43 phosphorylates and activates DAF-16, thus promoting its nuclear localization. The phosphorylation of DAF-16 at S286 by UNC-43 is removed by TAX-6•CNB-1, leading to DAF-16 inactivation. Mammalian FOXO3 is also regulated by CAMKIIA and Calcineurin.
Introduction:
Multiple signaling pathways, including insulin/IGF-1 signaling( IIS), germline signaling, mitochondrial signaling, and the signaling pathways induced by dietary restriction, regulate aging in C. elegans( Kenyon, 2005; Greer and Brunet, 2008). The best characterized is the IIS pathway, which includes the upstream insulin/IGF-1 receptor DAF-2 and the downstream FOXO transcription factor DAF-16. Signals from DAF-2 are transmitted through AGE-1( phosphoinositide 3-kinase) and PDK-1( phosphoinositol-dependent kinase-1) to AKT-1, AKT-2, and SGK-1, which phosphorylate DAF-16 and prevent it from translocating to the nucleus to activate a pro-longevity gene network. Reduction-of-function mutations of the kinase genes in the IIS pathway, from daf-2 to akt-1, akt-2, and sgk-1, all extend lifespan in a daf-16-dependent manner( Kenyon et al., 1993; Morris et al., 1996; Kimura et al., 1997; Hertweck et al., 2004). Lifespan extension by reduced IIS is also observed in other species, including flies and mice, indicating that the pathway is conserved evolutionarily( Kenyon, 2005; Greer and Brunet, 2008). Compared with the kinases in the C. elegans IIS pathway, little is known about the protein phosphatases that neutralize the effects of the kinases. The only known example is PPTR-1, a B56 regulatory subunit of PP2A, which directs PP2A to dephosphorylate AKT-1 at T350, thereby inactivating the kinase( Padmanabhan et al., 2009). DAF-18, the C. elegans PTEN, is a phosphatidylinositol 3, 4, 5-trisphosphate( PIP3) 3-phosphatase( Ogg and Ruvkun, 1998). The phosphatase for DAF-2 has not been identified, nor the one that regulates DAF-16. Previously, loss-of-function( lf) mutants for tax-6 and cnb-1, which encode the catalytic and regulatory subunits of C. elegans Calcineurin, respectively, were found to live longer than wild-type( WT) worms( Dong et al., 2007). In mammalian systems, Calcineurin( PP2B) is a Ca2+/calmodulin-dependent serine/threonine protein phosphatase that has diverse functions and affects both T cell activation and heart development( Crabtree, 1999). In C. elegans, Calcineurin regulates body size, thermotaxis, muscle contraction, and lifespan( Bandyopadhyay et al., 2002; Kuhara et al., 2002; Lee et al., 2004; Dong et al., 2007). The longevity phenotype of tax-6( lf) is partially dependent on daf-16( Dong et al., 2007). More recent studies have shown that C. elegans Calcineurin can regulate lifespan by suppressing autophagy( Dwivedi et al., 2009) or inactivating CRTC-1, a co-activator of CREB( Mair et al., 2011). However, direct targets of worm Calcineurin have not been identified. In the current work, we addressed how worm Calcineurin TAX-6•CNB-1 regulates lifespan. We discovered that DAF-16 was phosphorylated and activated by UNC-43 at the serine 286( S286) site. The phosphoryl group was removed by TAX-6•CNB-1. UNC-43 and TAX-6•CNB-1 therefore regulate C. elegans lifespan through the reversible phosphorylation of DAF-16. This regulatory mechanism has a different mode of action from the canonical IIS pathway because the phosphorylation activates, rather than represses, DAF-16. Activation of DAF-16 by UNC-43 occurs in response to different types of stress signals, such as heat, starvation, and oxidation. UNC-43 and TAX-6•CNB-1 can regulate DAF-16 independently of IIS, and the two signaling mechanisms appear to crosstalk, leading to coordinated action on DAF-16. We also show that the regulation of FOXO by CAMKII and Calcineurin is conserved in mammalian cells.
Discussion:
Our data suggest that CAMKII( UNC-43) and Calcineurin( TAX-6•CNB-1), by phosphorylating or de-phosphorylating serine 286 of DAF-16, extend or shorten the lifespan of C. elegans. The direct, antagonistic nature of these two enzymes also raised an interesting possibility that, with their opposing effects on DAF-16 and a common activating signal( Ca2+/CAM), UNC-43 and TAX-6•CNB-1 would constitutively negate each other and have essentially no control of DAF-16. However, this outcome most likely does not occur because of the difference in the spatial distribution and temporal activation profiles of the two enzymes. TAX-6 and CNB-1, similar to DAF-16, are expressed in most cells in C. elegans( Ogg et al., 1997; Bandyopadhyay et al., 2002; Kuhara et al., 2002; Dong et al., 2007). In contrast, unc-43 promoter-driven GFP was only detected in neurons and the intestine( Hunt-Newbury et al., 2007). We also detected UNC-43 primarily in the nervous system( not shown). At the subcellular level, the TAX-6::GFP fusion protein is distributed diffusely throughout the cytoplasm and inside the nucleus( Kuhara et al., 2002; Dong et al., 2007). In contrast, the CFP::UNC-43 fusion protein is concentrated on perinuclear structures and clusters in neurites( Umemura et al., 2005). Temporally, Ca2+-activated CAMKII phosphorylates another molecule of CAMKII at T286 to convert it to a Ca2+/CAM-independent kinase, prolonging the kinase activity after the initial activation( Erickson et al., 2011). CAMKII can also be activated by ROS at low Ca2+ concentrations( Erickson et al., 2011). In mammalian cells, inhibition of Calcineurin by cytoplasmic CAMKII and inhibition of CAMKII by Calcineurin have both been reported( MacDonnell et al., 2009; Kubokawa et al., 2011), suggesting that the balance is intricately maintained. Therefore, in the case of the simultaneous activation of CAMKII and Calcineurin by Ca2+/CAM, either the kinase or the phosphatase could dominate the regulation of DAF-16 either locally( e. g., cytoplasm vs nucleus) or for certain time windows. This balance likely fine-tunes the DAF-16 activity in response to a changing environment. It is likely that UNC-43/Calcineurin is responsible for activating DAF-16 when worms experience a variety of stress signals, including heat stress, oxidative stress, or prolonged starvation( Figure 6G). Food deprivation acts through UNC-43 to suppress spontaneous sex-muscle contraction in C. elegans males( LeBoeuf et al., 2007). Reported in HEK293T cells, human FOXO3 is phosphorylated at non-AKT sites under stress conditions such as heat shock or H2O2 treatment( Brunet et al., 2004). ROS-induced oxidation of two methionine residues activates CAMKII, and this activation can occur under conditions of low Ca2+( Erickson et al., 2011). Thus, CAMKII is perfectly equipped to transmit ROS signaling and calcium signaling, and phosphorylation of FOXO3 by CAMKII may play a highly conserved role in the stress response, from worms to humans. To date, DAF-16 is the only biochemically and genetically proven substrate of TAX-6•CNB-1, but it is not the only substrate involved in lifespan regulation by Calcineurin. Inactivation of CRTC-1, a coactivator of CREB, contributes to the longevity of tax-6( lf) animals( Mair et al., 2011). Hence, CRTC-1 is an excellent candidate, although it has not been shown that TAX-6•CNB-1 directly dephosphorylates CRTC-1. There may be additional substrates. Regardless, the discoveries made thus far jointly provide a good explanation for the large but incomplete suppression of tax-6( lf) longevity by daf-16( null)( Dong et al., 2007). Post-transplant new-onset diabetes mellitus( NODM) is a frequent and serious complication for organ transplant patients. One of the NODM risk factors is the use of Calcineurin inhibitors, such as cyclosporin A and FK506, which suppress immune-rejection of donor organs( Heisel et al., 2004). In light of this work, we propose that sustained activation of FOXO3 resulting from chronic inhibition of Calcineurin may cause NODM in transplant patients. Given the conservation and broad tissue distribution of CAMKII, Calcineurin, and FOXO3, the regulatory mechanism uncovered in this study likely plays a role in many physiological functions.
Although aging might seem to be a passive process—resulting simply from wear and tear over a lifetime—it can actually be accelerated or slowed down by genetic mutations . This phenomenon has been most thoroughly studied in the nematode worm , Caenorhabditis elegans . Normally , this worm lives for just two or three weeks , but genetic mutations that reduce the activity of certain enzymes in a series of biochemical reactions known as the insulin/IGF-1 signalling pathway can extend its lifespan by up to a factor of ten , and similar effects have been seen in flies and mice . Lifespans can also be increased by blocking other signalling pathways or restricting the intake of calories . This increase in lifespan associated with the insulin/IGF-1 signalling pathway is known to involve a protein called DAF-16 and two kinases called AKT-1 and AKT-2 . Under normal conditions the AKT kinases add several phosphate groups to the DAF-16 , which prevents it from travelling to the nucleus of the cell . However , when genetic techniques are used to block the insulin/IGF-1 signalling pathway , the AKT kinases are unable to add the phosphate groups; this leaves the DAF-16 free to enter the nucleus , where it activates a network of genes that promotes longevity . In addition to kinases , the insulin/IGF-1 signalling pathway also involves enzymes called phosphatases that remove the phosphate groups from other proteins . In particular , a phosphatase called calcineurin is known to be involved in the regulation of lifespan , but the details of this process are not fully understood . Now , Tao et al . have carried out a series of genetic and biochemical experiments to determine how phosphatases exert their influence on aging . The results show that calcineurin targets DAF-16 , the same protein that is targeted by the AKT kinases . Moreover , another kinase also targets DAF-16 when the worm is exposed to heat , starvation or some other form of stress: this kinase , which is not involved in the insulin/IGF-1 signalling pathway , is called CAMKII . Tao et al . show that these kinases act on DAF-16 in different ways: CAMKII activates it by adding the phosphate group at a specific site known as S286 , whereas the AKT kinases deactivate DAF-16 because they add phosphate groups at different sites , thereby preventing it from entering the nucleus . Calcineurin neutralizes the effect of CAMKII by removing the phosphate group at S286 to deactivate the DAF-16 . In addition to shedding new light on the regulation of lifespan in C . elegans , the new results could improve our understanding of aging in humans , and also the development of diabetes and other age-related diseases , because the equivalent molecules in mammalian cells are regulated in similar ways .