Gelino, Sara et al. (2009) International Worm Meeting "Role of autophagy in C. elegans longevity pathways."

Lapierre, Louis, Ong, Binnan, Hansen, and Malene, Gelino, Sara, McQuary, Philip

[International Worm Meeting, 2009]

C. elegans lifespan is modulated by multiple genetic pathways and processes. These include the DAF-2/insulin/IGF-1-like and TOR pathways, dietary restriction, protein translation and mitochondrial activity (reviewed in 1). Whereas our molecular understanding of these pathways comprises intricate roles for multiple transcription factors, including the transcription factors DAF-16/FOXO, PHA-4/FOXA, SKN-1 and HSF-1 (2, 3), much less is known about the downstream cellular events. The cellular process of autophagy has recently been linked to aging in C. elegans. During autophagy, cytoplasm and organelles in the cell is degraded and recycled (4). We and others have shown that autophagy is required for at least some of the known C. elegans longevity pathways (see references in 1). For example, autophagy genes are essential for the long life of dietary-restricted animals and these animals have increased levels of autophagy. In contrast, autophagy does not appear to play a critical role in the extended lifespan observed in animals with mutations in genes involved in protein translation (5). We have continued to investigate the role of autophagy in the known longevity pathways in C. elegans. For example, we find that the autophagy gene bec-1, the worm ortholog of the yeast and mammalian autophagy gene ATG6/VPS30/beclin 1, affects specific stress responses frequently observed in long-lived animals, such as thermotolerance. These results, along with our efforts to better characterize autophagy in C. elegans, will be discussed. 1. Melendez, Hall and Hansen, Methods Enzymol, 2008 2. Kenyon, Cell, 2005 3. Mair and Dillin, Annu Rev Biochem, 2008 4. Levine and Kroemer, Cell, 2008 5. Hansen et al., PLoS Genetics, 2008.

Lapierre, Louis R. et al. (2013) International Worm Meeting "HLH-30/TFEB is a conserved regulator of autophagy and modulates longevity in C. elegans."

De Magalhaes Filho, C. Daniel, Chu, Chu-Chiao, McQuary, Philip R., Ong, Binnan, Irazoqui, Javier E., Gelino, Sara, Davis, Andrew, Visvikis, Orane, Lapierre, Louis R., Hansen, Malene, Dillin, Andrew, Chang, Jessica T.

[International Worm Meeting, 2013]

The cellular recycling process of autophagy is emerging as an important conserved modulator of aging. Autophagy is critical for lifespan extension induced by selected genetic mutations or by nutrient deprivation in C. elegans, but the mechanism(s) by which this occurs remains unclear. Although several transcription factors such as DAF-16/FOXO and PHA-4/FOXA are known to promote longevity, no single transcription factor has been shown to regulate autophagy in these long-lived C. elegans models. Here we show that the C. elegans helix-loop-helix transcription factor HLH-30, a predicted ortholog of the mammalian transcription factor EB (TFEB), not only regulates autophagy but also plays a critical role in lifespan extension. We found that, similar to TFEB, HLH-30 translocates to the nucleus via a mechanism dependent on the conserved autophagy regulator and longevity determinant TOR, where it modulates the expression of multiple autophagy-related genes. Consistent with a role for autophagy in aging, overexpression of HLH-30 extends lifespan and hlh-30 is required for the long lifespan of all known autophagy-dependent longevity models in C. elegans, including dietary restriction. Similarly, we see Tfeb expression upregulated and nuclear localized in liver of dietary-restricted mice, raising the possibility that HLH-30/TFEB influences lifespan in a conserved manner by inducing autophagic flux. Our results thus demonstrate a conserved role for TFEB in regulating autophagy and identify HLH-30 as a novel longevity-modulating transcription factor.

Karla Opperman et al. (2007) International Worm Meeting "A structure-function analysis of the C. elegans L1CAMs."

Lihsia Chen, Xuelin Wang, Karla Opperman, Shan Zhou

[International Worm Meeting, 2007]

Cell adhesion molecules play important roles during development and in maintaining tissue integrity. L1CAMs are a family of immunoglobulin (Ig)-like cell adhesion molecules that are important in vertebrate nervous system development. L1CAMs are conserved in C. elegans, and are encoded by the lad-1/sax-7 and lad-2 genes. SAX-7 and LAD-2 have distinct functions in the nervous system despite overlapping neuronal expression. SAX-7 is required to maintain neuronal positioning while LAD-2 participates in axon pathfinding. We are performing a structure-function analysis to determine how both proteins mediate their functions. Because the cytoplasmic tails between both proteins are distinct, we are focusing our analysis on how the cytoplasmic tail regulates L1CAM functions. Indeed, while the extracellular domains of SAX-7 and LAD-2 are conserved, the LAD-2 cytoplasmic tail is completely divergent and does not contain any of motifs conserved in SAX-7 and vertebrate L1CAMs. These motifs include the ankyrin-binding motif, which links L1CAMs to the spectrin-actin cytoskeleton, the PDZ-binding motif, and conserved tyrosine residues that are phosphorylated. Our preliminary results reveal that both conserved motifs, as well as phosphorylation one of the tyrosine residues, which regulates ankyrin binding, all contribute to the function of SAX-7 in neuronal position maintenance. (1) Chen L, Ong B, Bennett V. J Cell Biol. 2001 Aug 20;154(4):841-55. (2) Wang X, Kweon J, Larson S, Chen L. Dev Biol. 2005 Aug 15;284(2):273-91. (3) Sasakura H, Inada H, Kuhara A, Fusaoka E, Takemoto D, Takeuchi K, Mori I. EMBO J. 2005 Apr 6;24(7):1477-88. Epub 2005 Mar 17.